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A Study of PDR001 in Combination With LCL161, Everolimus or Panobinostat

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02890069
Recruitment Status : Recruiting
First Posted : September 7, 2016
Last Update Posted : April 10, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE May 9, 2016
First Posted Date  ICMJE September 7, 2016
Last Update Posted Date April 10, 2019
Actual Study Start Date  ICMJE October 14, 2016
Estimated Primary Completion Date November 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 31, 2016)
  • Phase 1: Incidence of dose limiting toxicities (DLTs) [ Time Frame: During the first two cycles ]
    cycle = 28 days
  • Frequency of dose interruptions and reductions [ Time Frame: Through study completion, an average of 6 months ]
  • Frequency and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Through study completion, an average of 6 months ]
  • Changes between baseline and post-baseline laboratory parameters and vital signs [ Time Frame: Through study completion, an average of 6 months ]
  • Dose intensities [ Time Frame: Through study completion, an average of 6 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02890069 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 15, 2018)
  • Quantification of Tumor Infiltrating Lymphocytes (TILs) by Hematoxylin [ Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months) ]
    cycle = 28 days
  • Changes from baseline in ECG parameters in patients recieving PDR001 in combination with Panobinostat [ Time Frame: Baseline and end of treatment, an average of 6 months ]
  • Best overall response (BOR) [ Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Time to reach max concentration (Tmax) for PDR001 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Presence of anti-PDR001 antibodies [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Progression free survival (PFS) per RECIST v1.1 [ Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Treatment Free Survival (TFS) [ Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Maximum and minimum plasma concentrations of LCL161 (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Maximum and minimum Plasma concentrations of everolimus (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Maximum and minimum plasma concentrations of panobinostat (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Concentration of anti-PDR001 antibodies [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Characterization of TILs and myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate) [ Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months) ]
    Cycle = 28 days
  • Quantification of Tumor Infiltrating Lymphocytes (TILs) by eosin (H&E) stain [ Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months) ]
    cycle = 28 days
  • Maximum and minimum serum concentration of PDR001 (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for PDR001, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Progression free survival (PFS) per irRC [ Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for LCL161, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Time to reach max concentration (Tmax) for LCL161 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Time to reach max concentration (Tmax) for Everolimus [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Time to reach max concentration (Tmax) for Panobinostat [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for Everolimus, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for Panobinostat, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Maximum and minimum Plasma concentrations of QBM076 (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Maximum and minimum Plasma concentrations of HDM201 (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Time to reach max concentration (Tmax) for QBM076 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Time to reach max concentration (Tmax) for HDM201 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for QBM076, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for HDM201, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment)
Original Secondary Outcome Measures  ICMJE
 (submitted: August 31, 2016)
  • Quantification of Tumor Infiltrating Lymphocytes (TILs) by Hematoxylin [ Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months) ]
    cycle = 28 days
  • Changes from baseline in ECG parameters [ Time Frame: Baseline and end of treatment, an average of 6 months ]
  • Best overall response (BOR) [ Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Time to reach max concentration (Tmax) for PDR001 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Presence of anti-PDR001 antibodies [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Progression free survival (PFS) per RECIST v1.1 [ Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Treatment Free Survival (TFS) [ Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Maximum and minimum plasma concentrations of LCL161 (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Maximum and minimum Plasma concentrations of everolimus (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Maximum and minimum plasma concentrations of panobinostat (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Concentration of anti-PDR001 antibodies [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Characterization of TILs and myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate) [ Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months) ]
    Cycle = 28 days
  • Quantification of Tumor Infiltrating Lymphocytes (TILs) by eosin (H&E) stain [ Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months) ]
    cycle = 28 days
  • Maximum and minimum serum concentration of PDR001 (Cmax and Cmin) [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for PDR001, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Progression free survival (PFS) per irRC [ Time Frame: T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months ]
    cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for LCL161, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Time to reach max concentration (Tmax) for LCL161 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Time to reach max concentration (Tmax) for Everolimus [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
  • Time to reach max concentration (Tmax) for Panobinostat [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for Everolimus, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
  • Area under the concentration-time curve calculated to the last concentration point (AUClast) for Panobinostat, as applicable [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months ]
    T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of PDR001 in Combination With LCL161, Everolimus or Panobinostat
Official Title  ICMJE Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability and Pharmacodynamics (PD) of PDR001 in Combination With LCL161, Everolimus (RAD001) or Panobinostat (LBH589)
Brief Summary The purpose of this study is to combine the PDR001 checkpoint inhibitor with several agents with immunomodulatory activity to identify the doses and schedule for combination therapy and to preliminarily assess the safety, tolerability, pharmacological and clinical activity of these combinations.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Colorectal Cancer, Non-small Cell Lung Carcinoma (Adenocarcinoma), Triple Negative Breast Cancer, Renal Cell Carcinoma
Intervention  ICMJE
  • Biological: PDR001
    anti-PD1 antibody
  • Drug: LCL161
  • Drug: Everolimus
    Other Name: RAD001
  • Drug: Panobinostat
    Other Name: LBH589
  • Drug: QBM076
  • Drug: HDM201
Study Arms  ICMJE
  • Experimental: CRC - PDR001 + LCL161
    Dose escalation completed; expansion arm.
    Interventions:
    • Biological: PDR001
    • Drug: LCL161
  • Experimental: NSCLC - PDR001 + LCL161
    Dose escalation completed, expansion arm.
    Interventions:
    • Biological: PDR001
    • Drug: LCL161
  • Experimental: TNBC - PDR001 + LCL161
    Dose escalation completed, expansion arm.
    Interventions:
    • Biological: PDR001
    • Drug: LCL161
  • Experimental: CRC - PDR001+ Everolimus
    Dose escalation completed, expansion arm.
    Interventions:
    • Biological: PDR001
    • Drug: Everolimus
  • Experimental: NSCLC - PDR001+ Everolimus
    Dose escalation completed, expansion arm.
    Interventions:
    • Biological: PDR001
    • Drug: Everolimus
  • Experimental: TNBC - PDR001+ Everolimus
    Dose escalation completed, expansion arm.
    Interventions:
    • Biological: PDR001
    • Drug: Everolimus
  • Experimental: CRC - PDR001 + Panobinostat
    Enrollment to this combination arm is closed to further enrollment.
    Interventions:
    • Biological: PDR001
    • Drug: Panobinostat
  • Experimental: NSCLC - PDR001 + Panobinostat
    Enrollment to this combination arm is closed to further enrollment.
    Interventions:
    • Biological: PDR001
    • Drug: Panobinostat
  • Experimental: TNBC - PDR001 + Panobinostat
    Enrollment to this combination arm is closed to further enrollment.
    Interventions:
    • Biological: PDR001
    • Drug: Panobinostat
  • Experimental: CRC - PDR001 + QBM076
    Dose escalation.
    Intervention: Drug: QBM076
  • Experimental: TNBC - PDR001 + QBM076
    Dose escalation.
    Intervention: Drug: QBM076
  • Experimental: NSCLC- PDR001 + QBM076
    Dose escalation.
    Intervention: Drug: QBM076
  • Experimental: CRC - PDR001 + HDM201
    Dose escalation.
    Intervention: Drug: HDM201
  • Experimental: RCC - PDR001 + HDM201
    Dose escalation.
    Intervention: Drug: HDM201
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 8, 2019)
400
Original Estimated Enrollment  ICMJE
 (submitted: August 31, 2016)
350
Estimated Study Completion Date  ICMJE December 19, 2019
Estimated Primary Completion Date November 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent prior to any procedure
  • Patients with advanced/metastatic cancer, with measurable disease as determined by RECIST version 1.1, who have progressed despite standard therapy or are intolerant to SOC, or for whom no standard therapy exists. Patients must fit into one of the following groups:

    • CRC •NSCLC • TNBC• RCC

  • ECOG ≤ 2
  • Patient must have a site of disease for biopsy, and be a candidate for tumor biopsy according to the institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and again during therapy on this study.
  • Prior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to prior PD-1- or PD-L1-directed therapy did not lead to discontinuation of therapy.

Exclusion Criteria:

  • Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy within prior 2 weeks.
  • Patients with known hypersensitivity to any of the components of an investigational treatment will be excluded from participation in the corresponding arm but are eligible for participation in other study arm; Patients that have a history of hypersensitivity to rapamycin derivatives will be excluded from participation in the everolimus arm
  • History of or current drug-induced interstitial lung disease or pneumonitis grade ≥2
  • Out of range lab values as defined in protocol
  • Impaired cardiac function or clinically significant cardiac disease
  • Active, known or suspected autoimmune disease
  • Human Immunodeficiency Virus (HIV), or active Hepatitis C (HCV) virus. Escalation: active Hepatitis B (HBV); Expansion: Patients with Chronic HBV currently on medication will not be excluded.
  • Impairment of gastrointestinal (GI) function
  • Malignant disease, other than that being treated in this study
  • Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity and washout period is 6 weeks; prior immunotherapy - washout is 4 weeks
  • Active infection requiring systemic antibiotic therapy.
  • Patients requiring chronic treatment with systemic steroid therapy, other than replacement dose steroids or treatment with low, stable dose of steroid (<10 mg/day prednisone or equivalent) for stable CNS metastatic disease.
  • Patients receiving systemic treatment with any immunosuppressive medication.
  • Major surgery within 2 weeks of the first dose of study treatment
  • Radiotherapy within 2 weeks of the first dose of study drug
  • Participation in an interventional, investigational study within 2 weeks of the first dose of study treatment.
  • Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior therapy.
  • Use of hematopoietic colony stimulating growth factors </= 3 weeks prior to first dose

Additional exclusion criteria for PDR001/LCL161

  • Patients requiring medications metabolized through CYP3A4/5 and have a narrow therapeutic index or medications that are CYP3A4 substrates that cause QT prolongation
  • Patients requiring treatment with strong CYP2C8 inhibitors

Additional exclusion criteria for PDR001/Everolimus

  • Patients requiring treatment with moderate CYP3A4 inhibitors
  • Patients requiring treatment with a strong CYP3A4 inhibitor or inducer

Additional exclusion criteria for PDR001/Panobinostat-

  • Patient who received DAC inhibitors
  • Patient needing valproic acid during the study or within 5 days prior to first dose
  • Patients requiring medications that are sensitive CYP2D6 substrates areCYP2D6 substrates with a narrow therapeutic index or are anti-arrhythmic drugs/drugs with QT-prolongation risks
  • Patients requiring a strong inhibitor or inducer of CYP3A4
  • Clinically significant, uncontrolled heart disease and/or recent cardiac event within 6 months prior to study
  • Unresolved diarrhea ≥ CTCAE grade 2 or a medical condition associated with chronic diarrhea
  • Taking medications with QT prolongation risk or interval or inducing Torsade de pointes

Additional exclusion criteria for PDR001/QBM076-

  • Patients requiring medications that are strong inducers or strong inhibitors of CYP3A4
  • Patients requiring medications with narrow therapeutic index CYP3A4 substrates
  • Women using any form of hormonal contraception (oral, injected, implanted, transdermal) will be excluded (unless they are willing to switch to another effective form of contraception under their physician's guidance)

Additional exclusion criteria for PDR001/HDM201-

  • Prior treatment with compounds with the same mode of action as proposed for HDM201, i.e. an inhibition of the interaction of TP53 with HDM2, e.g. RG7112 or CGM097
  • Patients who require the following treatments moderate to strong CYP3A4 inhibitors; any substrates of CYP3A4/5 with a narrow therapeutic index
  • Moderate to strong CYP3A4 inducers
  • Patients having out of range values for:

Absolute neutrophil count (ANC) <1500/µL; Platelets < 100 000/µL

Other protocol-defined inclusion exclusion criteria may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111
Listed Location Countries  ICMJE Germany,   Korea, Republic of,   Netherlands,   Spain,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02890069
Other Study ID Numbers  ICMJE CPDR001X2102
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP