| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| systemic sclerosis associated with interstitial lung disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Tissue disease involving changes in the skin, blood vessels and internal organs. It is an'autoimmune disorder', meaning the immune system mistakenly attacks and destroys healthy body tissue. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025109 |
| E.1.2 | Term | Lung involvement in systemic sclerosis |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of pomalidomide QD compared to placebo in subjects with SSc-ILD
To evaluate the long-term safety and tolerability of pomalidomide (CC- 4047) QD in subjects with SSc-ILD
To evaluate the change from Baseline (Week 0) in the FVC in SSc-ILD subjects treated with pomalidomide QD compared to placebo
To evaluate the change from Baseline (Week 0) in the mRSS in SSc-ILD subjects treated with pomalidomide QD compared to placebo
To evaluate changes from Baseline (Week 0) in GI symptomatology as measured by the UCLA SCTC GIT 2.0 total score in SSc-ILD subjects treated with pomalidomide QD compared to placebo |
|
| E.2.2 | Secondary objectives of the trial |
To characterize the PK of pomalidomide in subjects with SSc-ILD
To evaluate the long-term clinical efficacy of PO pomalidomide (CC- 4047) QD in subjects with SSc-ILD
To evaluate the clinical efficacy of pomalidomide QD compared to placebo on dyspnea and oxygen saturation |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female subjects between 18 and 80 at the time of signing the ICD
2.Body weight ≥80pounds (36.3kg) at Screening and Baseline
3.Understand and voluntarily sign ICDs prior to the initiation of any study-related assessments/procedures
4.Able to adhere to the study visit schedule and other protocol requirements
5.Diagnosis of SSc as defined by ACR criteria. Subjects will be further classified into lSSc and dSSc based on the criteria presented in Appendix A.
6.Onset of the first non-Raynaud’s manifestation of SSc within 7 years of Screening
7. Subjects are required to meet at least one of the following 2 pulmonary-related criteria to be eligible for the study:
-FVC readings ≥ 45% and < 70% at Screening and Baseline (Visit 2) [with or without a documented pre-specified FVC decline or fibrosis score]
OR
-FVC readings ≥ 70% and ≤ 80% at Screening and Baseline (Visit 2) with a documented history of either or both of:
a) A ≥ 5% decrease (expressed as percent predicted or in liters) in FVC in the 24-month period prior to Baseline (Visit 2) based on 3 or more assessments. Two
assessments may be done during the Screening phase provided the assessments are completed at least 2 weeks apart.
b) An HRCT fibrosis score > 20%
8.Repeat FVC at Baseline within 5% of the FVC measured at Screening
9.DLco ≥ 35% and <or= 80% of predicted value at Screening (Documented DLco assessment within 6 months of Screening is acceptable. Test must be repeated prior to randomization if results are not available).
10.Abnormalities on HRCT consistent with parenchymal changes encountered in SSc: honeycombing or reticular changes with or without ground glass. These changes are usually symmetrical and are often in subpleural and basal locations. Some involvement of both lungs is required.
11.Must meet the following laboratory criteria:
-Hemoglobin ≥10.0 g/dL
-White blood cell (WBC) count ≥ 3000 /microL (≥ 3.0 x 109/L) and <or=14,000/microL (<or= 14 x 109/L)
-Absolute neutrophil count (ANC) ≥ 2 x 109/L
-Platelet count ≥ 150,000 /microL (≥ 150 X 109/L)
-MDRD eGFR ≥ 60 mL/min
-Total bilirubin <or= 2.0 mg/dL
-Albumin ≥ 3.0 g/dL
-Aspartate transaminase and alanine transaminase ≤ 1.5 X upper limit of normal
-Negative hepatitis B surface antigen is required. Subjects may have a positive anti-hepatitis B core antibody if the anti-hepatitis B surface antibody is positive as well
12.Females of childbearing potential must undergo pregnancy testing based on the frequency outlined in Appendix H and pregnancy results must be negative.
13.Unless practicing complete abstinence from heterosexual intercourse, sexually active FCBP must agree to use adequate contraceptive methods as specified in Appendix H.
-Abstinence is only acceptable in cases where this is the preferred and usual lifestyle of the subject. Periodic abstinence (calendar ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable.
14.Males (including those who have had a vasectomy) must use barrier contraception (condoms) when engaging in sexual activity with FCBP as specified in Appendix H.
15.Males must agree not to donate semen or sperm for the duration specified in Appendix H.
16.All subjects must:
-Understand that the IP could have a potential teratogenic risk.
-Agree to abstain from donating blood while taking IP and following discontinuation of investigational product
-Agree not to share IP with another person.
-Other than the subject, FCBP and males able to father a child should not handle the IP or touch the capsules, unless gloves are worn.
-Be counseled about pregnancy precautions and risks of fetal exposure.
17.Use of the following concomitant medications is permitted. These include:
-Proton pump inhibitors or other gastroesophageal reflux disease therapies
-Angiotensin receptor blocker therapies
-Angiotensin-converting enzyme inhibitor therapies
-Selective serum reuptake inhibitors
-Calcium channel blockers
-Non-sedating oral or intranasal antihistamine agents (intermittent usage)
-Oral statin agents for hyperlipidemia
-PDE5 inhibitors (if not being taken for pulmonary arterial hypertension )
-Endothelin-1 inhibitors (eg, bosentan) or prostaglandin analogues (eg, iloprost) for digital ulcers if taken for at least 28 days (prior to Screening (subjects may not have a diagnosis of PAH requiring treatment)
-≤ 10 mg/day of oral prednisone (or equivalent)
-Analgesic or opioid pain medications
-Cough medications
-One-a-day vitamins or supplements recommended by the physician for a deficiency are permitted. All others health supplements and herbal remedies are not allowed.
-Subjects currently taking concomitant medications which can prolong the QT/QTc interval may continue on their medications if their dosage(s) has been stable for at least 28 days prior to Baseline and there is no evidence of pathological QT/QTc prolongation on Screening or Baseline ECGs.
|
|
| E.4 | Principal exclusion criteria |
1.Oxygen saturation<92%(room air [sea level] at rest) at Screening or Baseline
2.Known diagnosis of obstructive lung disease as defined by FEV1/FVC ratio <0.7
3.Diagnosis of pulmonary arterial hypertension (PAH) requiring treatment
4.Known diagnosis of other significant respiratory disorders
5.Any significant medical condition, laboratory abnormality or psychiatric illness that would prevent the subject from participating in the study
6. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
7.Any condition that confounds the ability to interpret data from the study
8.Pregnant or lactating females
9.Current clinical diagnosis of another inflammatory connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis, primary Sjogren's syndrome, etc.) Subjects having Sjogren's syndrome secondary to SSc are eligible.
10.History of a thromboembolic event
11.Family history of genetic disease associated with deep vein thrombosis or thromboembolism
12. History of clinically significant endocrinologic, pulmonary (other than SSc-related), GI (other than SSc-related), neurologic, psychiatric, hepatic, renal, hematologic, cardiovascular, immunologic or other major uncontrolled disease
13.History or current diagnosis of peripheral neuropathy
14.History of alcohol or drug abuse
15.History of any of the following cardiac conditions within 6 months of Screening: acute myocardial infarction, acute coronary syndrome, new onset atrial fibrillation, new onset atrial flutter, second- or third-degree atrioventricular block, ventricular fibrillation, ventricular tachycardia, heart failure, cardiac surgery, interventional cardiac catheterization (with or without a stent placement), interventional electrophysiology procedure, presence of implanted permanent pacemaker or presence of implanted defibrillator
16.History of additional risk factors for torsade de pointes
17.Corrected QTcF>440msec on 2 of 3 Screening or BaselineECGs (predose)
18. Presence of any of the following on 2 of the 3 Screening or Baseline ECGs (pre-dose) at rest: heart rate<45beats/min or >110beats/min, PR interval>220ms, QRS duration>110ms
19.Clinically significant abnormality on any 2 of 3 Screening or Baseline ECGs
20.History of tuberculosis
21.History of HIV infection
22.History of congenital and acquired immunodeficiencies
23.Hepatitis B surface antigen positive. A positive anti-HBc without a positive anti-HBs at Screening
24.Antibodies to hepatitis C at Screening
25.History of malignancy
Prior treatments
26.Use of concomitant medication(s) which could increase the risk for developing deep vein thrombosis
27.Use of melphalan within 52 weeks of Screening
28.The addition of concomitant medications associated with QT prolongation during the course of the study
29.Use of any anti-coagulant or anti-thrombotic medications (other than low dose-aspirin [(<or=100 mg/day). In the event of hospitalization, a subject may use anti-coagulant or anti-thrombotic medications instead of low-dose aspirin, if it is felt to be in the best medical interest of the subject. Aspirin therapy should be reinstituted as soon as the Investigator feels it is medically appropriate.
30.Use of any cytotoxic/immunosuppressive agent (other than prednisone ≤ 10 mg/day [mean dose] or equivalent), including but not limited to azathioprine, cyclophosphamide, methotrexate, mycophenolate and cyclosporine within 28 days (4 weeks) of Screening
31.Use of prostaglandin analogues (eg, epoprostenol, iloprost, treprostinil) for PAH within 28 days (4 weeks) of Screening
32.Use of any biologic agent within 84 days (12 weeks) or 5 half-lives of Screening. In the case of rituximab, use within 168 days (24 weeks) of Screening or no recovery of
CD20-positive B lymphocytes if the last dose of rituximab has been more than 168 days (24 weeks) prior to Screening
33.Use of bosentan, ambrisentan, sildenafil, tadalafil and macitentan for PAH within 28 days (4 weeks) of Screening
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Treatment phase:
Safety (type, frequency, severity and relationship of AEs to pomalidomide, laboratory, ECG, physical exam or other changes) and tolerability to pomalidomide
Change from Baseline (Week 0) of the FVC at Week 52
Change from Baseline (Week 0) of the mRSS score at Week 52
Change from Baseline (Week 0) of the UCLA SCTC GIT 2.0 total score at
Week 52
Open-label Extension Phase:
Safety (type, frequency, severity and relationship of AEs and SAEs to pomalidomide, laboratory, ECG, physical exam or other changes) and tolerability to pomalidomide |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Treatment phase:
Safety:
- complete physical exam: week 24, week 52, week 56
- Laboratory: week 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56
- ECG: baseline, week 4, 6, 8, 12, 20, 28, 36, 44, 52 and 56
- adverse events: everyweek from week 1 to 56
- survival: every 6 months during the long-term follow-up phase, up to 5 years from treatment initiation.
FVC: week 52
mRSS: week 52
UCLA SCTC GIT: week 52
Open Label extension: See tables 2 and 3 of protocol for full details
-Targeted Physical exam, YR 1 weeks 54,56,60,64,72,80,88,96,104
-Vital signs, Pregnancy tests, Adverse events, Assessment for
malignancy, Concomitant meds and procedures, Pomalidomide
counseling :
Yr 1 weeks,
52,53,54,55,56,58,60,62,64,68,72,76,80,84,88,92,96,100,104 |
|
| E.5.2 | Secondary end point(s) |
Treatment phase:
Estimation of pomalidomide PK parameters in plasma, eg, AUCt, Cmax, and tmax (Sparse PK mandatory, Intensive PK only for patients who consent)
Change from Baseline (Week 0) of the FVC at Weeks 12, 24, 36 and 48
Change from Baseline (Week 0) of the mRSS at Weeks 12 and 24
Change from Baseline (Week 0) UCLA SCTC GIT 2.0 total scores at Weeks 12 and 24
Change from Baseline (Week 0) UCLA SCTC GIT 2.0 subscale scores (Reflux, Distention/Bloating, Fecal Soilage, Diarrhea, Social functioning, Emotional Wellbeing and Constipation) at Weeks 12, 24 and 52
Change from Baseline (Week 0) of the oxygen saturation (as measured by pulse
oximetry) at Weeks 12, 24 and 52
Change from Baseline (Week 0) dyspnea (as measured by the Transition Dyspnea Index) at Weeks 12, 24 and 52
Open-label Extension Phase
-Change from Baseline (Week 0) and Week 52 of the FVC at Weeks 64,
76, 88, 100, 104, 128 and 156
- Change from Baseline (Week 0) and Week 52 of the mRSS at Weeks 64, 76, 104, 128 and 156
-Change from Baseline (Week 0) and Week 52 of the UCLA SCTC GIT 2.0 total score at Weeks 64, 76, 104, 128 and 156
- Change from Baseline (Week 0) and Week 52 of the UCLA SCTC GIT 2.0 subscale scores (Reflux, Distention/Bloating, Fecal Soilage, Diarrhea, Social functioning, Emotional Well-being and Constipation) at Weeks 64, 76, 104, 128 and 156
-Change from Baseline (Week 0) and Week 52 of the oxygen saturation (as measured by pulse oximetry) at Weeks 64, 76, 104, 128 and 156
-Change from Baseline (Week 0) and Week 52 dyspnea (as measured by the Transition Dyspnea Index) at Weeks 64, 76, 104, 128 and 156 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Sparse PK assessments: weeks 1 to 4, weeks 6 and 8
Intensive PK assessments: Baseline and week 6
FVC: baseline, Weeks 12, 24, 36 and 48
mRSS: baseline, weeks 12 and 24
UCLA SCTC GIT: baseline, weeks 12, 24, 52
Oxygen saturation: weeks 12, 24 and 52
Transition Dyspnea: weeks 12, 24, 52
Open-label Extension Phase
- FVC at Weeks 64, 76, 88, 100,104, 128 and 156
- mRSS at Weeks 64, 76, 104,128 and 156
-UCLA SCTC GIT 2.0 total score at Weeks 64, 76, 104, 128 and 156
- UCLA SCTC GIT 2.0 subscale scores (Reflux, Distention/Bloating, Fecal Soilage, Diarrhea, Social functioning, Emotional Well-being and Constipation) at Weeks 64, 76, 104, 128 and 156
-oxygen saturation at Weeks 64, 76, 104, 128 and 156
- dyspnea (Transition Dyspnea Index) at Weeks 64, 76, 104, 128 and 156 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| France |
| Germany |
| Italy |
| Poland |
| Russian Federation |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| For this study, the end-of-trial is defined as the date of the last visit of the last subject to complete the study or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the SAP, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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