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Study to Assess Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of RO7112689 in Healthy Volunteers and Participants With Paroxysmal Nocturnal Hemoglobinuria

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ClinicalTrials.gov Identifier: NCT03157635
Recruitment Status : Recruiting
First Posted : May 17, 2017
Last Update Posted : October 7, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This is a Phase I/II, first-in-human study consisting of 3 sequential parts and an open-label extension (OLE) in which the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single-doses of RO7112689 will be evaluated in healthy volunteers (HV) during Part I, and safety, tolerability, PK, and PD of RO7112689 will be evaluated in participants with PNH during Parts 2, 3, and OLE of the study. Efficacy of RO7112689 will be evaluated in Parts 2 and 3.

Condition or disease Intervention/treatment Phase
Paroxysmal Hemoglobinuria, Nocturnal Drug: RO7112689 Drug: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 49 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An Adaptive Phase I/II Study to Assess Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of RO7112689 in Healthy Volunteers and Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Actual Study Start Date : November 14, 2016
Estimated Primary Completion Date : January 28, 2020
Estimated Study Completion Date : May 16, 2023


Arm Intervention/treatment
Experimental: Part 1 (Healthy Volunteers): RO7112689
Healthy participants will receive a single dose of RO7112689 in each dose-escalation cohort of Part 1. RO7112689 will be administered at a starting dose of 75 milligrams (mg). Doses are planned to be escalated up to Cohort 5.
Drug: RO7112689
RO7112689 will be administered as per schedule described in individual arm.

Placebo Comparator: Part 1 (Healthy Volunteers): Placebo
Healthy participants will receive a single dose of RO7112689 matching placebo in each dose-escalation cohort of Part 1.
Drug: Placebo
Placebo will be administered as per schedule described in Part 1 placebo arm.

Experimental: Part 2 (PNH Participants): RO7112689
PNH participants will receive 3 single ascending doses of RO7112689 on Days 1, 8, and 22 followed by weekly RO7112689 administrations up to a maximum of 5 months. Weekly RO7112689 administrations will start no earlier than Day 36. The starting dose of Part 2 will be based on data from Part 1 of the study.
Drug: RO7112689
RO7112689 will be administered as per schedule described in individual arm.

Experimental: Part 3 (PNH Participants): RO7112689
PNH participants will receive RO7112689 at dose and regimen based on data from Part 2 of the study, for a maximum treatment duration of 5 months.
Drug: RO7112689
RO7112689 will be administered as per schedule described in individual arm.

Experimental: OLE (PNH Participants): RO7112689
PNH participants who participated in Parts 2 and 3, and who derive clinical benefit from RO7112689 may enroll into OLE. Participants will initially receive the same dose regimen as they were receiving in Parts 2 and 3, respectively followed by dose regimen based on emerging safety, PK, and PD data from Parts 2 and 3, for up to a maximum treatment duration of two years from entry into OLE.
Drug: RO7112689
RO7112689 will be administered as per schedule described in individual arm.




Primary Outcome Measures :
  1. Part 1: Percentage of Participants With Dose-Limiting Events (DLEs) [ Time Frame: Baseline up to approximately 3 months ]
  2. Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to approximately 3 months ]
  3. Parts 2, 3: Percentage of Participants With AEs and SAEs [ Time Frame: Baseline up to approximately 8 months ]
  4. Part 2: Percentage of Participants With Terminal Complement Activity, as Assessed by Ex Vivo Liposome Lysis in Serum Using the Liposome Immunoassay (LIA) [ Time Frame: Baseline up to Day 224 ]
  5. Part 3: Percentage of Participants With Terminal Complement Activity, as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA [ Time Frame: Baseline up to Day 224 ]
  6. OLE: Percentage of Participants With AEs and SAEs [ Time Frame: OLE: Week 21 up to Week 129 ]

Secondary Outcome Measures :
  1. Part 1: Percentage of Participants With Terminal Complement Activity, as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA [ Time Frame: Part 1: Baseline up to Day 91 (assessed at predose [Hr 0], end of infusion [EOI] [1 Hr], Hr 2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 84, 91) ]
  2. Part 2: Serum Lactate Dehydrogenase (LDH) Levels [ Time Frame: Predose (Hr0), Hr 10-12 on Days 1, 8; Days 2, 5, 9, 15, 22, 29, 36, 43, 50, 64, 78, 92, 106, 120, 134, 224 ]
  3. Part 3: Serum LDH Levels [ Time Frame: Part 3: Predose (Hr 0), Hr 10-12 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 57, 71, 85, 99, 113, 127, 134; Day 224 ]
  4. Part 1: Total Complement Component 5 (C5) Concentration [ Time Frame: Part 1: Predose (Hr 0), EOI (1 Hr), Hr 2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 84, 91 ]
  5. Part 2: Total C5 Concentration [ Time Frame: Part 2: Predose (Hr 0), EOI (1 Hr), Hr 2, 6, 10-12 on Day 1; Days 2, 5, 9, 15, 29, 224; predose [Hr 0], EOI [1 Hr], Hr 10-12 on Days 8, 22; predose [Hr 0] on Day 36, 43, 50, 64, 78, 92, 106, 120, 134 ]
  6. Part 3: Total C5 Concentration [ Time Frame: Part 3: Predose (Hr 0), EOI (1 Hr), Hr 2, 6 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99, 113, 134; Day 224 ]
  7. Part 1: Target C5 Concentration [ Time Frame: Part 1: Predose (Hr 0), EOI (1 hr), Hr2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 84, 91 ]
  8. Part 2: Target C5 Concentration [ Time Frame: Part 2: Predose (Hr 0), EOI (1 Hr), Hr 2, 6,10-12 on Day 1; Days 2, 5, 9, 15, 29, 224; predose [Hr 0], EOI [1 Hr], Hr 10-12 on Days 8, 22; predose [Hr 0] on Day 36, 43, 50, 64, 78, 92, 106, 120, 134 ]
  9. Part 3: Target C5 Concentration [ Time Frame: Part 3: Predose (Hr 0), EOI (1 hr), Hr 2, 6 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99, 113, 134; Day 224 ]
  10. Part 2: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Day 8, 22, 36, 50 and 64 [ Time Frame: Baseline, Day 8, 22, 36, 50, 64 ]
  11. Part 3: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 2, 8, 15, 29, 57 [ Time Frame: Baseline, Day 2, 8, 15, 29, 57 ]
  12. Part 2: Change From Baseline in Health-Related Quality of Life (HRQoL) as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Score at Day 8, 22, 36, 50, and 64 [ Time Frame: Baseline, Day 8, 22, 36, 50, 64 ]
  13. Part 3: Change From Baseline in HRQoL as Measured by EORTC QLQ-C30 Score at Day 2, 8, 15, 29, 57 [ Time Frame: Baseline, Day 2, 8, 15, 29, 57 ]
  14. Part 2: Participant Treatment Satisfaction as Measured by Treatment Satisfaction Questionnaire for Medication (TSQM) Score at Day 8, 22, 36, 50 and 64 [ Time Frame: Baseline, Day 8, 22, 36, 50, 64 ]
  15. Part 3: Participant Treatment Satisfaction as Measured by TSQM Score at Day 2, 8, 15, 29, 57 [ Time Frame: Baseline, Day 2, 8, 15, 29, 57 ]
  16. Part 2: Number of Packed Red Blood Cell (RBC) Units Transfused per Participant [ Time Frame: Baseline up to Day 224 ]
  17. Part 3: Number of Packed RBCs Units Transfused per Participant [ Time Frame: Baseline up to Day 224 ]
  18. Part 2: Percentage of Participants With Packed RBC Units Transfused [ Time Frame: Baseline up to Day 224 ]
  19. Part 3: Percentage of Participants With Packed RBC Units Transfused [ Time Frame: Baseline up to Day 224 ]
  20. Part 1: Percentage of Participants With Anti-Drug Antibodies (ADAs) to RO7112689 [ Time Frame: Part 1: Day 1 up to Day 91 (assessed at predose [Hour 0] on Day 1; on Days 14, 28, 56, 84, and 91) ]
  21. Part 2: Percentage of Participants With ADAs to RO7112689 [ Time Frame: Part 2: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8; on Days 29, 50, 106, 134, and 224) ]
  22. Part 3: Percentage of Participants With ADAs to RO7112689 [ Time Frame: Part 3: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 29, 57, 99, 134; on Day 224) ]
  23. OLE: Percentage of Participants With Terminal Complement Activity, as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA [ Time Frame: OLE: Weeks 36, 52, 68, 84, 100, 116 ]
  24. OLE: Serum LDH Levels [ Time Frame: OLE: Predose (Hr 0) on Weeks 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108; Week 116 ]
  25. OLE: Total C5 Concentration [ Time Frame: OLE: Predose (Hr 0) on Weeks 36, 52, 68, 84, 100; Week 116 ]
  26. OLE: Target C5 Concentration [ Time Frame: OLE: Predose (Hr 0) on Weeks 36, 52, 68, 84, 100; Week 116 ]
  27. Part 2: Time to First Packed RBC Unit Transfusion [ Time Frame: Baseline up to Day 224 ]
  28. Part 3: Time to First Packed RBC Unit Transfusion [ Time Frame: Baseline up to Day 224 ]
  29. Part 2: Time to Persistent Elevation of LDH [ Time Frame: Baseline up to Day 224 ]
  30. Part 3: Time to Persistent Elevation of LDH [ Time Frame: Baseline up to Day 224 ]
  31. Part 2: Percentage of Participants With LDH Below Upper Limit of Normal (ULN) [ Time Frame: Baseline up to Day 224 ]
  32. Part 3: Percentage of Participants With LDH Below ULN [ Time Frame: Baseline up to Day 224 ]
  33. Part 2: Percentage of Participants With Complement Suppression [ Time Frame: Baseline up to Day 134 ]
  34. Part 3: Percentage of Participants With Complement Suppression [ Time Frame: Baseline up to Day 134 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Part 1 (HVs only):

  • Healthy male volunteers, aged between 21 and 55 years inclusive
  • Participants with a negative hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody, and human immunodeficiency virus (HIV) test result
  • Participants who have been vaccinated against hepatitis B
  • No evidence of Neisseria meningococci in nasopharyngeal swab
  • Neisseria meningitidis vaccination against serogroups B and A, C, W, and Y
  • Non-smokers, or former smokers, who have not smoked for at least 60 days prior to screening

Parts 2 and 3 (PNH participants only):

  • Male or female participants with PNH between 18 and 75 years of age
  • Neisseria meningitidis vaccination in accordance with most current local guidelines or standard of care (SOC) for participants at increased risk for meningococcal disease (Part 2)
  • Participant has been vaccinated with Neisseria meningitidis vaccine(s) in accordance with most current local guidelines or SOC for participants at increased risk for meningococcal disease or is being revaccinated if applicable (Part 3)
  • Antibiotic prophylaxis for meningococcal infection must be initiated prior to initiation of RO7112689 therapy if the time period between initial Neisseria meningitidis vaccination and first dose of RO7112689 is less than 2 weeks (Part 2)
  • Antibiotic prophylaxis of meningococcal infection may be initiated prior to initiation of RO7112689 therapy based on local guidelines or SOC for participants at increased risk for meningococcal disease (Parts 2 and 3)
  • Stable dose for greater than or equal to (>/=) 28 days prior to screening of other therapies (immunosuppressant therapy, corticosteroids, iron supplements)

Part 2 only (currently untreated PNH participants who are candidates for treatment with complement inhibitors only):

  • PNH participants who have not been treated with any complement inhibitor or if previously treated stopped treatment due to lack of efficacy based on a single missense C5 heterozygous mutation
  • Serum LDH levels at least 1.5-fold above the ULN at screening
  • Hepatitis B participants can be enrolled if their liver function test values are less than 2 x ULN and there is no liver function impairment

Part 3 only (PNH participants currently treated with eculizumab only):

  • PNH participants who have been treated continuously with eculizumab for at least 3 months preceding enrollment in the trial
  • Participants receive regular infusions of eculizumab
  • Subjects with a negative hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test result

OLE only - PNH participants:

  • PNH participants who have completed Parts 2 and 3 respectively
  • PNH participants who derived, in the investigator's opinion, benefit from treatment with RO7112689

All Parts:

  • Male and female participants should use proper means of contraception

Exclusion Criteria:

Part 1 (HVs only):

  • Any clinically relevant history or the presence of moderate to severe respiratory, renal, hepatic, gastrointestinal, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, or connective tissue disease
  • Any major illness within 1 month before the screening
  • History of clinically significant hypersensitivity (example: drugs, excipients) or allergic reactions
  • History or presence of clinically significant electrocardiogram (ECG) abnormalities or cardiovascular disease
  • Any contra-indication for receiving Neisseria meningitides vaccination and antibiotic prophylaxis therapy as required in the study
  • Congenital or acquired complement deficiency
  • Carriers of Neisseria meningitides based on cultures from nasopharyngeal swabs
  • Known active viral, bacterial or fungal infection including herpes, herpes zoster or cold sores, during the last 14 days prior to first study drug administration
  • Signs of parasitic infection (example: eosinophilia, diarrhea)
  • History of significant recurrent infections in the opinion of the investigator

Parts 2 and 3 - PNH participants only:

  • Evidence of moderate to severe concurrent renal, liver, cardiac, pulmonary or gastrointestinal disease not related to PNH as determined by the investigator
  • History of an illness that, in the opinion of the study investigator, might confound the results of the study or that poses an additional risk to the participant by his or her participation in the study
  • History of bone marrow transplantation
  • Treatment with azathioprine or erythrocyte-stimulating agents within 14 days prior to first study drug administration

Part 3 - PNH patients only:

  • Any evidence of sero-positive auto-immune connective tissue diseases (such as systemic lupus erythematosus, or rheumatoid arthritis)
  • Any evidence of active inflammatory conditions (including inflammatory bowel disease, or cryoglobulinemia)

All Parts:

  • Under active therapy with intravenous immunoglobulin (IVIG)
  • Mentally incapacitated or history of a clinically significant psychiatric disorder over the previous 5 years
  • Known or suspected hereditary complement deficiency
  • Prior splenectomy
  • History of meningococcal meningitis
  • History of allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies or known hypersensitivity to any constituent of the product
  • Any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 28 days prior to screening or oral antibiotics within 2 weeks prior to screening and up to first study drug administration
  • History of or currently active primary or secondary immunodeficiency, including known history of human immunodeficiency virus (HIV) infection
  • Evidence of chronic active hepatitis C infection
  • Evidence of malignant disease including myelodysplastic syndrome, or malignancies diagnosed within the previous 5 years

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03157635


Contacts
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Contact: Reference Study ID Number: BP39144 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
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France
Institut hematologie Centre Hayem CHU paris Saint-Louis Lariboisiere F Widal Hopital St Louis Recruiting
Paris, France, 75475
Centre Hospitalier Lyon Sud Active, not recruiting
Pierre Benite, France, 69495
Germany
Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stammz Recruiting
Aachen, Germany, 52074
Universitätsklinikum Essen; Klinik für Hämatologie Recruiting
Essen, Germany, 45122
Elblandklinikum Riesa; Klinik fuer Haematologie Onkologie und Gastroenterologie Recruiting
Riesa, Germany, 1589
Universitätsklinikum Ulm; Institut für Klinische Transfusionsmedizin Recruiting
Ulm, Germany, 89081
Hungary
Semmelweis Egyetem, 1. Szamu Belgyogyaszati Klinika, Diabetologia Recruiting
Budapest, Hungary, 1083
Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology Recruiting
Kaposvar, Hungary, 7400
Italy
A.O. UNIVERSITARIA FEDERICO II DI NAPOLI;Dipartimento di Medicina Clinica e Chirurgia Recruiting
Napoli, Campania, Italy, 80136
Policlinico Universitario Agostino Gemelli Recruiting
Roma, Lazio, Italy, 00168
Ospedale Di Vicenza; Nefrologia, Ematologia Active, not recruiting
Vicenza, Veneto, Italy, 36100
Japan
Tohoku University Hospital Recruiting
Miyagi, Japan, 980-8574
Osaka University Hospital; Hematology and Oncology Recruiting
Osaka, Japan, 565-0871
NTT Medical Center Tokyo Recruiting
Tokyo, Japan, 141-8625
Tokyo Medical University Hospital Recruiting
Tokyo, Japan, 160-0023
Keio University Hospital Active, not recruiting
Tokyo, Japan, 160-8582
University of Tsukuba Hospital; Hematology Recruiting
Tsukuba, Japan, 305-8576
Korea, Republic of
Severance Hospital, Yonsei University Health System Recruiting
Seoul, Korea, Republic of, 03722
Asan Medical Center - Oncology Terminated
Seoul, Korea, Republic of, 05505
Seoul National University Hosp; Dept Internal Med Hem Onc Recruiting
Seoul, Korea, Republic of, 110-744
Netherlands
Pra International Group B.V Completed
Groningen, Netherlands, 9728 NZ
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

Additional Information:
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03157635     History of Changes
Other Study ID Numbers: BP39144
2016-002128-10 ( EudraCT Number )
First Posted: May 17, 2017    Key Record Dates
Last Update Posted: October 7, 2019
Last Verified: October 2019
Additional relevant MeSH terms:
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Hemoglobinuria
Hemoglobinuria, Paroxysmal
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Anemia, Hemolytic
Anemia
Hematologic Diseases
Myelodysplastic Syndromes
Bone Marrow Diseases