Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. Of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10-49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways.

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We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications. Chronic Obstructive Pulmonary Disease (COPD) is characterised by reduced lung function and is the third leading cause of death globally.

Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratios per standard deviation of the risk score (6 alleles) (95% confidence interval) 1.24 (1.20-1.27), P=5.05x10 -49) and we observed a 3.7 fold difference in COPD risk between highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in development, elastic fibres and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications. Maximally attained lung function and subsequent lung function decline together determine the risk of developing Chronic Obstructive Pulmonary Disease (COPD). COPD, characterised by irreversible airflow obstruction and chronic airway inflammation, is the third leading cause of death globally.

Smoking is the primary risk factor for COPD but not all smokers develop COPD and more than 25% of COPD cases occur in never-smokers. Patients with COPD exhibit variable presentation of symptoms and pathology, with or without exacerbations, with variable amounts of emphysema and with differing rates of progression. Although risk factors for COPD are known, including smoking and environmental exposures in early, and later life, the causal mechanisms are not well understood. Disease-modifying treatments for COPD are required. Understanding genetic factors associated with reduced lung function and COPD susceptibility could inform drug target identification, risk prediction and stratified prevention or treatment. Previous genome-wide association studies (GWAS) of COPD identified several independent COPD-associated variants – but the rate and scale of discovery has been limited by available sample sizes. We conducted a powerful GWAS for lung function, and followed up the robustly-associated variants in COPD case-control studies.

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Although previous GWAS have reported genome-wide significant associations with lung function –, there has not been a comprehensive study confirming the effect of these variants on COPD susceptibility. In this study, we hypothesised that: (i) undertaking GWAS of lung function of unprecedented power and scale would detect novel loci associated with quantitative measures of lung function; (ii) collectively these variants would be associated with the risk of developing COPD, and (iii) aggregate analyses of all novel and previously-reported signals of association, and the identification of genes through which their effects are mediated, would reveal further insight into biological mechanisms underlying the associations. Together these findings could provide potential novel targets for therapeutic intervention and pinpoint existing drugs which could be candidates for repositioning for the treatment of COPD. 43 new signals for lung function For stage 1, genome-wide association analyses of forced expired volume in 1 second (FEV 1), forced vital capacity (FVC) and FEV 1/FVC were undertaken in 48,943 individuals from the UK BiLEVE study who were selected from the extremes of the lung function distribution in UK Biobank (total n=502,682). From analysis of 27,624,732 variants, 81 independent variants associated with one or more traits with P.

Stage 1 and stage 2 association results for the 43 novel signals of association with lung function. Using the stage 1 results, a 95% ‘credible set’ of variants (i.e. The set of variants that were 95% likely to contain the underlying causal variant, based on Bayesian refinement) was defined for all (novel and previously reported) association signals for which this was feasible (67 signals, and ); 13 of these signals were fine-mapped to A (near ZKSCAN3, FEV 1; conditional β (s.e.) = -0.058 (0.01), P=1.26x10 -9, ) and rs2070600:CT (in AGER, FEV 1/FVC; conditional β (s.e.) = 0.120 (0.013), P=4.23x10 -20, ),. We identified that 29 of the lung function-associated signals had previously shown genome-wide significant association in GWAS of traits other than lung function or COPD. This included associations with inflammatory bowel disease (Crohn’s disease and/or ulcerative colitis, 3 signals) and height (9 signals, 3 of which showed a consistent direction of effect on height and the lung function measure with which they were most strongly associated). With the exception of KANSL1, there was no significant (P.

95 variants and COPD susceptibility The disease-relevance of lung function-associated variants has been questioned. Therefore we tested association with COPD susceptibility for variants representing 95 of the 97 lung function associated signals in up to 20,086 COPD cases and 215,630 controls (data were unavailable for further study for the X-chromosome variant, rs7050036:AT near AP1S2, and a rare variant, chr33:CT).

Clinical trials The European Union Clinical Trials Register allows you to search for protocol and results information on:. interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);. clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.

Learn including the source of the information and the legal basis. The EU Clinical Trials Register currently displays 31915 clinical trials with a EudraCT protocol, of which 5148 are clinical trials conducted with subjects less than 18 years old. The register also displays information on 18700 older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006). Cardiac monitoring: an ECHO scan (or MUGA scan) was performed at screening, at the end of the CRT period and every 8 weeks during the maintenance phase. For subjects who had a decreased LEVF during the CRT and/or maintenance period, the ECHO or MUGA scans were performed in the follow-up period.

Liver chemistry monitoring and follow-up criteria were implemented in order to follow up on any potential hepatobiliary disorders that may occur. Hepatic function was to be monitored every 4 weeks during treatment and stopping rules were defined for severe hepatic events. An IDMC (Independent Data Monitoring Committee) convened to review accumulating safety (every six months) and efficacy (DFS) (only at pre-planned interim, futility analysis) data and to provide an opportunity to terminate the study early in case of any concerns regarding safety and/or efficacy. Modification of the Timing of the primary analysis: with the plateauing of investigator observed DFS events, it was decided to conduct the primary analysis with fewer events than originally planned and to discontinue DFS assessments to reduce burden and exposure to invasive tests and scans for patients still in DFS follow-up. Upon approval of amendment 04, patients on DFS follow-up moved to survival follow-up. Regarding compliance and study medication administration, subjects were allowed to take tablets as a suspension, in recognition of the particular difficulty some patients affected by SCCHN and its treatment could experience in swallowing tablets. Diarrhea Management guidelines/ recommendation were provided to Investigators to help managing any potential diarrhea AE - Radiotherapy (RT) Quality Assurance program: in order to standardize RT practice an independent vendor qualified each site, provided RT guidelines, and reviewed the RT plan for every subject.

Arm description Participants received placebo per oral monotherapy once daily (QD) for 1 week, followed by radiotherapy of 2 Gray (Gy) per day for 5 days per week (for a total dose of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 milligrams per meters squared (mg/m^2) intravenously (IV) on Days 1, 22, and 43 of radiotherapy. One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received placebo per oral administration QD, followed by maintenance placebo per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner.

Arm description Participants received lapatinib 1500 mg per oral monotherapy QD for 1 week, followed by radiotherapy of 2 Gy per day for 5 days per week (for a total of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 mg/m^2 IV on Days 1, 22, and 43 of radiotherapy.

One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received lapatinib 1500 mg per oral administration QD, followed by maintenance lapatinib 1500 mg per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner. Reporting group description Participants received placebo per oral monotherapy once daily (QD) for 1 week, followed by radiotherapy of 2 Gray (Gy) per day for 5 days per week (for a total dose of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 milligrams per meters squared (mg/m^2) intravenously (IV) on Days 1, 22, and 43 of radiotherapy. One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received placebo per oral administration QD, followed by maintenance placebo per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner. Reporting group description Participants received lapatinib 1500 mg per oral monotherapy QD for 1 week, followed by radiotherapy of 2 Gy per day for 5 days per week (for a total of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 mg/m^2 IV on Days 1, 22, and 43 of radiotherapy. One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received lapatinib 1500 mg per oral administration QD, followed by maintenance lapatinib 1500 mg per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner.

Reporting group description Participants received placebo per oral monotherapy once daily (QD) for 1 week, followed by radiotherapy of 2 Gray (Gy) per day for 5 days per week (for a total dose of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 milligrams per meters squared (mg/m^2) intravenously (IV) on Days 1, 22, and 43 of radiotherapy. One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received placebo per oral administration QD, followed by maintenance placebo per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner. Reporting group description Participants received lapatinib 1500 mg per oral monotherapy QD for 1 week, followed by radiotherapy of 2 Gy per day for 5 days per week (for a total of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 mg/m^2 IV on Days 1, 22, and 43 of radiotherapy.

One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received lapatinib 1500 mg per oral administration QD, followed by maintenance lapatinib 1500 mg per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner. Participants received lapatinib 1500 mg per oral monotherapy QD for 1 week, followed by radiotherapy of 2 Gy per day for 5 days per week (for a total of 66 Gy for up to 7 weeks).

Participants received concurrent cisplatin 100 mg/m^2 IV on Days 1, 22, and 43 of radiotherapy. One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received lapatinib 1500 mg per oral administration QD, followed by maintenance lapatinib 1500 mg per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner. End points Primary: Disease free survival (DFS). DFS is defined as the time from randomization until the earliest date of disease recurrence (evidence of local, regional, or distant disease progression, second primary tumor) or death due to any cause. Disease recurrence was based on the assessments from the blinded, independent reviewer (radiological and clinical). Who initiated alternative anti-cancer therapy prior to disease recurrence or death were treated as censored at the last assessment prior to the time of this initiation.

Whose disease did not recur or who did not die, DFS was censored at the time of the last independently assessed radiological scan (where initiation of alternative anti-cancer therapy had not commenced). Who missed =2 consecutive disease assessments were censored at the last assessment prior to the missed assessments.

Considered to have malignant disease at Baseline were censored at the time of randomization. 99999 represents NA - insufficient number of events to calculate value. TTLR is defined as the time from randomization until the first occurrence that local and/or regional recurrence is documented or the date of censor. Local relapse is defined as recurrent cancer in the primary tumor bed not clearly attributable to a second primary neoplasm.

Regional relapse is defined as recurrent cancer in the neck not clearly attributable to a second primary neoplasm. All other events prior to locoregional recurrence were treated as competing risks at the time they occured. All other participants were treated as censored at the time of their last disease assessment. Participants with malignant disease at Baseline according to the independent review were censored at the time of randomization for the analysis of independently reviewed data. 99999 represents NA - insufficient number of events to calculate value. TTDR is defined as the time from randomization until the first occurrence that distant relapse is documented.

Distant relapse is defined as clear evidence of distant metastases (lung, bone, brain, etc.). Metastasis is defined as the spread of a cancer from one organ or part to another non-adjacent organ or part. All other events prior to a distant relapse were treated as competing risks at the time they occured.

All other participants were treated as censored at the time of their last disease assessment. Participants with malignant disease at Baseline according to the independent review were censored at the time of randomization for the analysis of independently reviewed data. 99999 represents NA - insufficient number of events to calculate value. Participants who developed a second primary tumor at the time of the first recurrence or within 28 days of the first recurrence were measured. The criteria for a second primary tumor are as follows: a distinct lesion separated from the primary tumor site by 2 centimeters of normal epithelium; or a new cancer with different histology; or any cancer, regardless of site, occurring =3 years after initial treatment. Participants with baseline disease were included in the denominator when calculating the percentage. Extent of exposure is defined as the duration of treatment administered during the study.

The mean duration of treatment is calculated as the number of days between the start of treatment and the end of treatment inclusive (i.e., treatment stop date minus treatment start date + 1). Participants were counted in a treatment phase (monotherapy, chemoradiotherapy, and maintenance) if they had received any dose in that phase. Participants randomized to placebo who received =1 dose of lapatinib in error were included in the lapatinib arm. Safety Population (SP): all par. Who were randomized and took =1 dose of study medication. Available at the specified time points were analyzed (represented by n=X, X in the category titles).

Different par. May have been analyzed for different parameters, so the overall number of par. Analyzed reflects everyone in the SP.

From randomization until end of 1year maintenance treatment (average of 63 study weeks) Notes 16 - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication. If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints.

Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations.

Refer to the General Adverse AE/SAE module for a complete list of non-serious AEs occurring at a frequency threshold of 5% and SAEs. From the first dose of lapatinib/placebo until 5 days after the last dose (average of 141 study weeks) Notes 19 - The end point is not reporting statistics for all the arms in the baseline period.

It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication. If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints. Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo).

The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. Data are summarized using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI CTC version 3.0) toxicity grades.

Data are reported as the number of par. Who had a grade 3 (G3) or grade 4 (G4) toxicity for the indicated chemistry parameters, where G3 indicates a severe toxicity and G4 indicates a life-threatening toxicity. Clinical chemistry parameters included: albumin, alkaline phosphatase (AP), alanine amino transferase (ALT), aspartate amino transeferase (AST), total bilirubin (TB), calcium, carbon dioxide content/bicarbonate (CO2/HCO3), creatinine, glucose, potassium, and sodium. The worst-case on-therapy visit includes any scheduled or unscheduled post-Baseline visit. Only those par. Available at the specified time points were analyzed (represented by n=X, X in the category titles). Different par.

May have been analyzed for different parameters, so the overall number of par. Analyzed reflects everyone in the Safety Population.

From Baseline (within 8 weeks prior to randomization Day 1) until the end of the maintenance period/early withdrawal (up to Study Week 64) Notes 22 - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication.

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If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints. Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. Data are summarized using the NCI CTC version 3.0 toxicity grades.

Data are reported as the number of participants who had a grade 3 (G3) or grade 4 (G4) toxicity for the indicated hematological parameters, where G3 indicates a severe toxicity and G4 indicates a life-threatening toxicity. The worst-case on-therapy visit includes any scheduled or unscheduled post-Baseline visit. Hematology parameter included: hemoglobin, total neutrophils (TN), platelet count (PC), and White Blood Cell (WBC) count. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population. From Baseline (within 8 weeks prior torandomization Day 1) until the end of the maintenance period/early withdrawal (up to Study Week 64) Notes 25 - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.

Justification: The safety population was taken as all participants who received one dose of medication. If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints.

Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. From 180 days after completion of radiation until the last follow-up/withdrawal visit (average of 64 study weeks) Notes 28 - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication. If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints.

Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. Blood pressure measurement included systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of CRT, MW 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, and at the time of withdrawal from IP.

Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population. Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of chemoradiotherapy (CRT), Maintenance Week (MW) 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, Withdrawal from investigational product (IP; up to Study Week 64) Notes 31 - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication. If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints.

Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. Heart rate (HR) was measured at Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of CRT, MW 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, and at the time of withdrawal from IP. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population. Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of chemoradiotherapy (CRT), Maintenance Week (MW) 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, Withdrawal from IP (up to Study Week 64) Notes 34 - The end point is not reporting statistics for all the arms in the baseline period.

It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication.

If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints. Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure.

Body temperature was measured at Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of CRT, MW 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, and at the time of withdrawal from IP. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population. Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of chemoradiotherapy (CRT), Maintenance Week (MW) 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, Withdrawal from IP (up to Study Week 64) Notes 37 - The end point is not reporting statistics for all the arms in the baseline period.

It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication.

If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints. Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. Body weight was measured at Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of CRT, MW 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, and at the time of withdrawal from IP.

Change from Baseline was calculated as the post-Baseline value minus the Baseline value.Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population. Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of chemoradiotherapy (CRT), Maintenance Week (MW) 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, Withdrawal from IP (up to Study Week 64) Notes 40 - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.

Justification: The safety population was taken as all participants who received one dose of medication. If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints. Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo).

The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. A 12-lead ECG was recorded at Baseline, at the end of the CRT, at Maintenance Week 56, at withdrawal from IP, and at anytime post-baseline. Data are presented as clinically significant (CS) or not clinically significant (NCS) abnormal findings. The study investigator determined if an abnormal ECG finding was CS or NCS.Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population. Baseline (BL; within 8 weeks prior to randomization Day 1), End of CRT, Maintenance Week 56, Withdrawal from IP, and at any time Post-Baseline (up to Study Week 64) Notes 43 - The end point is not reporting statistics for all the arms in the baseline period.

It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication.

If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints. Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. The Eastern Cooperative Oncology Group (ECOG) performance status scales and grades/criteria are used by doctors and researchers to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the participant, and to determine appropriate treatment and prognosis. Grade 0, fully active, able to carry on all pre-disease performance without restriction.

Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours.

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Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead. From Baseline (BL; within 8 weeks prior to randomization Day 1) until the end of the maintenance period/early withdrawal (up to Study Week 64) Notes 46 - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The safety population was taken as all participants who received one dose of medication. If a participant was randomized to the placebo arm and received any lapatinib in error, they were counted in the lapatinib arm in terms of safety endpoints.

Five subjects randomized to receive placebo were given lapatinib, and 3 randomized subjects did not receive any study medication (2 lapatinib, 1 placebo). The Lapatinib 1500 mg containing the Safety population was used for this outcome measure. Change from Baseline (BL) in quality of life status was assessed using the FACT-H&N questionnaire, which is designed to measure multidimensional quality of life in participants with head and neck cancer. Change from Baseline was analyzed using parametric analysis of covariance (with the Baseline value as a covariate). The FACT-H&N questionnaire contains 39 items (27 general questions and 12 head and neck cancer-specific items) covering 4 dimensions and 1 subscale: physical well-being, social/family well-being, emotional well-being, functional well-being, and a head and neck cancer subscale.

Possible subscale scores range from 0 to 36. Higher scores represent better quality of life. Data were adjusted for participant-reported quality of life scores at Baseline.

1.7 ± 0.4 Notes 49 - Safety Population. Only those par. Who had a BL and post-BL score at the time point were analyzed. 50 - Safety Population.

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Only those par. Who had a BL and post-BL score at the time point were analyzed. No statistical analyses for this end point Secondary: Change from Baseline in quality of life status as assessed by the Functional Assessement of Cancer Therapy-Head and Neck (FACT-H&N) questionnaire Secondary: Change from Baseline in quality of life status as assessed by the EuroQol-5D (EQ-5D) scale. Change from Baseline in quality of life status was assessed using the EQ-5D scale, a 5-item health status measure and a visual analog rating scale. Change from Baseline was analyzed using parametric analysis of covariance (with the Baseline value as a covariate).

The EQ-5D is a generic measure of self-reported health outcomes that is applicable to a wide range of health conditions and treatments. The EQ-5D covers health status in 5 domains (3 questions each): mobility, self-care, usual activities, pain or discomfort, and anxiety or depression.

Each item is scored as follows: 1, no problems; 2, some moderate problems; 3, extreme problems. The possible EQ-5D index utility values range from 0.594 to 1, and the thermometer score ranges from 0 to 100. Higher scores represent better quality of life. Data were adjusted for participant-reported quality of life scores at Baseline. LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart with each contraction. LVEF was assessed using echocardiogram (ECHO: a test of the action of the heart using ultrasound waves to produce a visual display, for the diagnosis or monitoring of heart disease ) and multigated acqusition scans (MUGA scan: a noninvasive diagnostic test used to evaluate the pumping function of the ventricles).

Data from the ECHO and MUGA scans were combined, and the absolute change from Baseline (Abs) data are presented according to the following categories: No change or any increase, 0-=20% decrease, =10% decrease and =the Lower Limit of Normal (LLN), =10% decrease and below LLN, =20% decrease and =LLN, or =20% decrease and below LLN. The relative percent change from Baseline (Rel) data are presented according to the following categories: =20% decrease and =LLN and =20% decrease and below LLN.

Reporting group description Participants received placebo per oral monotherapy once daily (QD) for 1 week, followed by radiotherapy of 2 Gray (Gy) per day for 5 days per week (for a total dose of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 milligrams per meters squared (mg/m^2) intravenously (IV) on Days 1, 22, and 43 of radiotherapy. One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received placebo per oral administration QD, followed by maintenance placebo per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner. Reporting group description Participants received lapatinib 1500 mg per oral monotherapy QD for 1 week, followed by radiotherapy of 2 Gy per day for 5 days per week (for a total of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 mg/m^2 IV on Days 1, 22, and 43 of radiotherapy.

One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received lapatinib 1500 mg per oral administration QD, followed by maintenance lapatinib 1500 mg per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner. Amendment No. 1: To provide further clarification on: (1) Radiological assessments: frequency and type updated to reflect current clinical practice; (2) Addition of fiberoptic endoscopy procedure in the assessments updated to reflect current clinical practice; (3) Inclusion criteria modification to include subjects that express all levels of ErbB1 based on current scientific evidence and application of testing methods; (4) Stratification criteria updates to nodal status, geographical region and ErbB1 expression (tumour site unchanged). Amendment No.

02: Global amendment to: Amend inclusion criteria to exclude subjects with a second primary tumour that has been resected at the same time as the original tumour. Exclusion criteria added to exclude patients with active hepatic disease. Add additional SAE definition, reporting criteria and follow-up assessments for hepatic toxicity. Add additional liver function assessments every 4 weeks Allow the use of carboplatin for subjects who cannot tolerate cisplatin (after consultation with the medical monitor). Clarify radiotherapy quality assurance process.

Clarify CT/MRI scan requirements. Remove requirement for brain scan unless clinically indicated. Clarify screening windows and requirements for bone scan and panendoscopy procedures. Clarify the dose modifications required in the event of toxicities. Clarify the dose of concurrent dexamethasone allowed.

Clarify the definition of the evaluable population. Clarify that all subjects will continue in the maintenance phase even if they may not qualify within the evaluable population. Remove the Serum EGFR assessments. Allow screening procedures to commence immediately following surgery. Allow a total screening window of 8 weeks between surgery and randomization, and, subsequently, a total 9 weeks window before starting lapatinib/placebo. Updates to statistical section; including a planned interim for futility following 50% of events, updated recruitment rates and clarification of the DFS endpoint.

Amend frequency of survival calls to approximately every 6 months. Clarify the follow-up of patients until disease progression. Clarify the follow-up of patients when they withdraw from IP. Confirmation that patients will be followed-up for a maximum of 5 years after last patient has been randomised. General corrections and clarifications to protocol text, including the abbreviations, study schema, and time and events table. Amendment No.

03: Global Amendment to: Update the Statistical section to: 1) Clarify the target patient accrual as 680; 2) Re-adjust the anticipated improvement in the DFS interval; 3) Increase the target number of DFS ITT events to 298; 4) Update the target number of events for non-binding interim analysis for futility. Remove the Radiotherapy Protocol from Appendix 7 and referenced now in the Study Procedures Manual. Updated prohibited medications list. General corrections and clarifications to protocol text, including the abbreviations, and time and events table. Amendment No.: 04 Modified the timing for the primary analysis of the study (Rationale described in Section 1.2.4 ).

Moved patients currently in DFS follow-up into OS follow-up, hence removing the requirement for radiological scans and endoscopies. Described the planned overall survival analyses (Section 8.3.5). Stop study follow-up in the event of a non-significant primary analysis of DFS. Interruptions (globally) Were there any global interruptions to the trial?

No Limitations and caveats Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. None reported More information.