| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| 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 | 10042952 |
| E.1.2 | Term | Systemic rheumatoid arthritis |
| E.1.2 | System Organ Class | 100000004859 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the efficacy of multiple dose levels of IPI 145 compared to placebo in subjects with moderate-to-severe active rheumatoid arthritis (RA) taking a stable dose of methotrexate (MTX) |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
Evaluate the safety of multiple dose levels of IPI 145 compared to placebo in subjects with moderate-to-severe active RA taking a stable dose of MTX
Characterize the pharmacokinetics (PK) of IPI-145 in subjects with moderate-to-severe RA taking a stable dose of MTX
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| There is an optional sub study for Pharmacogenomics. There is not a separate protocol, it is included in the main protocol. |
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| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be eligible for participation in the study:
1. Male or female adults ≥18 and ≤70 years of age
2. Meet the 1987 ACR criteria for RA
3. ACR functional class I-III
4. Have ≥5 swollen AND ≥5 tender joints (based on 66 and 68 joint counts, respectively) at Screening and Baseline
5. C-reactive protein >7 mg/L (>1.4 x ULN for central laboratory) at Screening
6. Positive laboratory result at Screening for RF and/or ACPA
7. RA disease duration of at least 6 months
8. Must be taking MTX for at least 3 months prior to Screening, and on a stable dose and route for at least 6 weeks prior to dosing (Day 1); stable doses must be
- 7.5 to 25.0 mg once per week (split doses are permitted)
- if dose is <15 mg per week, then must have history of intolerance or toxicity at doses ≥15 mg per week
Must be willing to maintain the same MTX dose and route of administration through the final Follow-up Visit
9. Must be taking folic or folinic acid and willing to maintain a stable dose from Screening through the final Follow-up Visit
10. If taking sulfasalazine, chloroquine, or hydroxychloroquine, must be on stable doses from at least 8 weeks prior to Dosing (Day 1) and willing to maintain stable doses through final Follow-up Visit
11. If taking systemic steroids (such as prednisone), must be on a stable dose (≤ equivalent of 10 mg per day prednisone) within 4 weeks of dosing (Day 1) and willing to maintain stable dose through final Follow-up Visit
12. a. Sexually active women, unless surgically sterile (complete oophorectomy only) or at least 1 year post-menopausal (confirmed by FSH blood level at Screening), must have a negative serum pregnancy test result at Screening and agree to use two effective methods of contraception, one of which must be a barrier method, from the signing of informed consent form through 3 months after the last dose of study drug
b. Sexually active men, unless surgically sterile, must agree to use an effective method of birth control from the signing of informed consent form through 21 days after the last dose of study drug
13. Provide written informed consent prior to any study Screening procedures
14. Willing and able to complete all study requirements and study related restrictions through the final Follow-up Visit approximately 3 weeks after the last dose of study drug |
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| E.4 | Principal exclusion criteria |
Subjects are to be excluded from the study if they meet any of the following criteria:
1. Any prior treatment with a PI3K inhibitor in a previous clinical study
2. History of allergy or reaction to any component of the study drug formulation, such as excipients in the study drug capsule (See Section 7.1)
3. Use of more than 1 nonsteroidal anti-inflammatory drug (NSAID) or use of a single agent at a dose higher than indicated for treatment of RA within 4 weeks of dosing (Day 1) (note: any chronic NSAID dose must remain stable from 4 weeks prior to dosing [Day 1])
4. Previous failure or inadequate response to >2 biologic DMARDs
5. Use of the following medications to treat RA:
- oral or injectable gold, etanercept, anakinra, or tofacitinib within 30 days prior to dosing (Day 1)
- cyclosporine, azathioprine, abatacept, infliximab, tocilizumab or adalimumab within 60 days prior to dosing (Day 1)
- leflunomide within 180 days prior to dosing (Day 1), unless receipt of appropriate course of cholestyramine for washout (cholestyramine 8 g TID for 11 days) at least 30 days prior to dosing (Day 1)
- cyclophosphamide within 180 days prior to dosing (Day 1)
- rituximab within 180 days prior to dosing (Day 1); subjects with a history of rituximab use must have a normal CD19 count at Screening
- parenteral or intra-articular corticosteroids, or other immunosuppressive therapy within 30 days prior to dosing (Day 1)
- other immunosuppressive agents or non-biologic DMARD within 30 days or 5 half-lives (whichever is longer) prior to dosing (Day 1)
6. Concurrent administration of medications or foods known to be strong or moderate inhibitors or inducers of CYP3A (see Appendix 3).
7. Acute or ongoing clinically significant infection (includes, but not limited to, clinically significant upper respiratory tract infections and suspected tuberculosis) as determined by the Investigator within 4 weeks prior to Screening
8. Receipt of any live or attenuated vaccine within 30 days prior to dosing (Day 1)
9. Participation in another investigational drug study within 30 days prior to Screening, and willingness to refrain from participation in another investigational drug study until completion of the final Follow-up Visit
10. Clinically significant abnormalities on safety laboratory tests, 12-lead ECG, vital signs, physical examination or medical history at Screening or Baseline, based on the medical judgment of the Investigator; specific safety laboratory values for exclusion include
- Serum creatinine ≥2.0 mg/dL (177 μmol/L) or creatinine clearance <60 mL/min
- ALT, AST, or total bilirubin >1.5 x ULN [total bilirubin exclusion cut-off does not apply if subject has Gilbert’s Syndrome]
- Hemoglobin <10 g/dL, WBC <3.0 x 109/L, absolute neutrophil count <1.0 x 109/L, absolute lymphocyte count <1.0 x 109/L, or platelets <100×109/L
11. Evidence of active or prior hepatitis B or active hepatitis C infection at Screening
12. History of HIV infection, or known risk factors for HIV within 1 year of Screening (e.g., unprotected sexual intercourse with an HIV-infected individual) 1, 2
13. Positive or confirmed indeterminate screen result for active or latent tuberculosis (QuantiFERON-TB blood test at Screening)
14. History of or current pancreatitis (unless documented as due to gallstones, cholecystectomy has been performed, and no recurrence within 60 days prior to screening)
15. History of significant non-RA systemic disease (e.g., coronary artery disease, uncontrolled seizure disorder, cancer [except for adequately treated non-metastatic basal cell or squamous cell carcinomas of the skin or in situ cervical carcinoma], renal failure) as judged by the Investigator
16. Other significant rheumatologic disease (other than Sjögren's syndrome), uncontrolled autoimmune disease other than RA, or uncontrolled severe extra-articular RA disease (e.g., vasculitis)
17. Currently pregnant or lactating
18. History of drug or alcohol abuse within 1 year of Screening in the opinion of the Investigator
19. Major surgery, as determined by the Investigator, within 60 days prior to Screening, or planned elective surgery from Screening through the final Follow-up Visit
20. Anticipated need for a live or live-attenuated vaccination from Screening through the final Follow-up Visit
21. Subject is an employee or first-degree relative of an employee of the contract research organization (CRO), participating site, or Infinity Pharmaceuticals, Inc.
22. Ongoing stomatitis or ulceration of the gastrointestinal tract
23. Subjects who, in the opinion of the Investigator, are at an increased risk for gastrointestinal perforation, lymphoproliferative disorder, or clinical immunosuppression
24. Active herpes zoster infection or a history of herpes zoster infection within 12 weeks of Screening |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who achieve a 20% improvement in the American College of Rheumatology Criteria (ACR20) from Baseline to Week 12 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to week 12. |
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| E.5.2 | Secondary end point(s) |
• Proportion of subjects who achieve an ACR20 over Week 4 through Week 12, based on a repeated measures model
• Proportion of subjects who achieve an ACR20 from Baseline to Weeks 2, 4, 6, 8, and 10
• Proportion of subjects who achieve a 50% improvement in ACR Criteria (ACR50) from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12
• Proportion of subjects who achieve a 70% improvement in ACR Criteria (ACR70) from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12
• Change in the number of tender/painful joints from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12 (68 joint count)
• Change in the number of swollen joints from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12 (66 joint count)
• Change in the health assessment questionnaire disability index (HAQ-DI) from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12
• Change in subject assessment of pain from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12 (VAS 100 mm)
• Change in subject global assessment of disease activity from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12 (VAS 100 mm)
• Change in physician global assessment of disease activity from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12 (VAS 100 mm)
• Change in C-reactive protein (CRP) from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12
• Change in the 3-variable Disease Activity Score in 28 joints (DAS28)-CRP from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12
• Proportion of subjects who achieve a response on the DAS28-CRP from Baseline to each of Weeks 2, 4, 6, 8, 10, and 12
Safety Endpoints:
• Adverse events (AEs)
• Safety laboratory findings
PK Endpoints:
• Pharmacokinetic parameters derived from plasma IPI-145 concentrations
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline through to week 12 (every two weeks) |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | 4 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Bulgaria |
| Colombia |
| Germany |
| Hungary |
| Mexico |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Ukraine |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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