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ALXN1210 (Ravulizumab) Versus Eculizumab in Complement Inhibitor Treatment-Naïve Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

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ClinicalTrials.gov Identifier: NCT02946463
Recruitment Status : Active, not recruiting
First Posted : October 27, 2016
Results First Posted : February 12, 2019
Last Update Posted : May 15, 2020
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Brief Summary:
The primary purpose of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult participants with PNH who had never been treated with a complement inhibitor (treatment-naïve).

Condition or disease Intervention/treatment Phase
Paroxysmal Nocturnal Hemoglobinuria (PNH) Biological: Ravulizumab Biological: Eculizumab Phase 3

Detailed Description:

The study consisted of a 4-week screening period and a 26-week randomized treatment period (Primary Evaluation Period). After completion of the 26-week Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive ravulizumab for up to 5 years.

This study is ongoing. The data presented is for the Primary Evaluation Period. The results for the Extension Period will be reported after study completion.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 246 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Open-Label, Active-Controlled Study of ALXN1210 Versus Eculizumab in Complement Inhibitor-Naïve Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Actual Study Start Date : December 20, 2016
Actual Primary Completion Date : January 25, 2018
Estimated Study Completion Date : January 2023


Arm Intervention/treatment
Experimental: Ravulizumab

Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligram (mg) on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.

Biological: Ravulizumab
All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to <60 kilogram (kg): 2400 mg was given as a single loading dose, followed by 3000 mg as maintenance dose. For participants weighing ≥60 to <100 kg: 2700 mg was given as a loading dose, followed by 3300 mg as maintenance dose. For participants weighing ≥100 kg: 3000 mg was given as a loading dose, followed by 3600 mg as maintenance dose.
Other Names:
  • ALXN1210
  • ULTOMIRIS

Active Comparator: Eculizumab

Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.

Biological: Ravulizumab
All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to <60 kilogram (kg): 2400 mg was given as a single loading dose, followed by 3000 mg as maintenance dose. For participants weighing ≥60 to <100 kg: 2700 mg was given as a loading dose, followed by 3300 mg as maintenance dose. For participants weighing ≥100 kg: 3000 mg was given as a loading dose, followed by 3600 mg as maintenance dose.
Other Names:
  • ALXN1210
  • ULTOMIRIS

Biological: Eculizumab
All treatments were given as IV infusions. Participants were administered induction doses of 600 mg followed by maintenance doses of 900 mg.




Primary Outcome Measures :
  1. Proportion Of Participants With Normalization Of Lactate Dehydrogenase (LDH) Levels [ Time Frame: Day 29 through Day 183 ]
    LDH is an indicator of intravascular hemolysis that occurs in patients with paroxysmal nocturnal hemoglobinuria (PNH). A decrease in LDH from above the upper limit of normal (ULN) to below the ULN indicates reduction (improvement) in hemolysis. Normalization of LDH levels (LDH-N) was LDH levels less than or equal to 1 x ULN, from Day 29 through Day 183. The ULN for LDH is 246 U/L.

  2. Percentage Of Participants Who Achieved Transfusion Avoidance (TA) [ Time Frame: Baseline through Day 183 ]
    Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines through Day 183.


Secondary Outcome Measures :
  1. Percentage Of Participants With Breakthrough Hemolysis (BTH) [ Time Frame: Baseline through Day 183 ]
    Breakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 gram/deciliter (g/dL)], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 × ULN, after prior LDH reduction to <1.5 × ULN on therapy.

  2. Percent Change From Baseline In Lactate Dehydrogenase (LDH) Levels [ Time Frame: Baseline, Day 183 ]
    Baseline is defined as the average of all available assessments of LDH levels prior to first study drug dose. Estimates are based on Mixed Model for Repeated Measures (MMRM) that includes treatment group, history of transfusion (as a categorical variable based on the stratification factor levels) and baseline LDH level (as a continuous variable), study visit and study visit by treatment group interaction. An unstructured covariance structure was used.

  3. Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue [ Time Frame: Baseline, Day 183 ]
    FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline is defined as the last non-missing value prior to first dose of study drug. Estimates are based on MMRM that includes treatment group, the observed stratification randomization indicators (history of transfusion and LDH) and baseline FACIT-Fatigue level, study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.

  4. Percentage Of Participants With Stabilized Hemoglobin Levels [ Time Frame: Baseline through Day 183 ]
    Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through Day 183.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female ≥18 years of age.
  2. PNH diagnosis confirmed by documented by high-sensitivity flow cytometry.
  3. Presence of 1 or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 gram/deciliter), history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cells (pRBC) transfusion due to PNH.
  4. Lactate dehydrogenase (LDH) level ≥1.5 times the upper limit of normal at screening.
  5. Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study treatment.
  6. Female participants of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab.
  7. Willing and able to give written informed consent and comply with study visit schedule.

Exclusion Criteria:

  1. Treatment with a complement inhibitor at any time.
  2. History of bone marrow transplantation.
  3. Body weight <40 kg.
  4. Females who are pregnant, breastfeeding, or who have a positive pregnancy test at screening or Day 1.
  5. Participation in another interventional clinical study or use of any experimental therapy within 30 days before initiation of study drug on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater.
  6. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or sponsor, would preclude participation.
  7. Unstable medical conditions (for example, myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, coexisting chronic anemia unrelated to PNH).

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): NCT02946463


Locations
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United States, California
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Los Angeles, California, United States, 90033
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Los Angeles, California, United States, 90048
United States, Texas
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Fort Worth, Texas, United States, 76104
Argentina
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Buenos Aires, Argentina, C1015ABO
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Buenos Aires, Argentina, C1425AUM
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Córdoba, Argentina
Australia
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Perth, Australia
Austria
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Linz, Austria
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Vienna, Austria
Belgium
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Hasselt, Belgium
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Leuven, Belgium
Brazil
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Belém, Brazil
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Rio de Janeiro, Brazil
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Salvador, Brazil
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São Paulo, Brazil, 05403-000
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São Paulo, Brazil, 08270-070
Canada
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Edmonton, Canada
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Toronto, Canada
Czechia
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Plzen, Czechia
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Praha, Czechia
Estonia
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Tallinn, Estonia
France
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Poitiers, Vienne, France
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Limoges, France
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Montpellier, France
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Paris, France
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Pierre-Bénite, France
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Rennes, France
Germany
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Essen, Germany
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Ulm, Germany
Italy
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Ascoli Piceno, Italy
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Firenze, Italy
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Milano, Italy
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Napoli, Italy
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Vicenza, Italy
Japan
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Bunkyō-Ku, Japan, 113-8431
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Bunkyō-Ku, Japan
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Fukuoka, Japan
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Fukushima, Japan
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Hamamatsu-shi, Japan
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Kanazawa-shi, Japan
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Koshigaya-shi, Japan
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Kumamoto, Japan
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Nishinomiya-shi, Japan
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Ogaki-shi, Japan
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Okayama-city, Japan
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Okayama-shi, Japan
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Osakasayama-shi, Japan
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Sapporo, Japan
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Shimotsuke-shi, Japan
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Shinagawa-Ku, Japan
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Shinjuku-Ku, Japan, 160-0023
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Shinjuku-Ku, Japan, 160-8582
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Suita-shi, Japan
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Tokorozawa-shi, Japan
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Toyoake-shi, Japan
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Tsukuba, Japan
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Wakayama-shi, Japan
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Yokohama-City, Japan, 227-8501
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Yokohama-City, Japan, 236-0004
Korea, Republic of
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Anyang-si, Korea, Republic of
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Busan, Korea, Republic of
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Daegu, Korea, Republic of
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Incheon, Korea, Republic of
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Jeonju, Korea, Republic of
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Jinju-si, Korea, Republic of
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Seoul, Korea, Republic of, 02841
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Seoul, Korea, Republic of, 03080
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Seoul, Korea, Republic of, 03722
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Seoul, Korea, Republic of, 04401
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Seoul, Korea, Republic of, 05505
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Seoul, Korea, Republic of, 06351
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Seoul, Korea, Republic of, 06591
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Seoul, Korea, Republic of, 07985
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Seoul, Korea, Republic of, 08308
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Suwon-si, Korea, Republic of, 16247
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Suwon-si, Korea, Republic of, 16499
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Ulsan, Korea, Republic of
Malaysia
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Kota Bharu, Kelantan, Malaysia
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Miri, Sarawak, Malaysia
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Sibu, Sarawak, Malaysia
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Ampang, Malaysia
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Johor Bahru, Malaysia
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Kota Bahru, Malaysia, 16150
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Kota Bharu, Malaysia, 15586
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Kota Kinabalu, Malaysia
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Kubang Kerian, Malaysia
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Kuching, Malaysia
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Pulau Pinang, Malaysia
Mexico
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Monterrey, Mexico
Poland
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Gdańsk, Poland
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Warsaw, Poland
Russian Federation
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Arkhangel'sk, Russian Federation
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Barnaul, Russian Federation
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Bryansk, Russian Federation
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Irkutsk, Russian Federation
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Kaluga, Russian Federation
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Kirov, Russian Federation
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Krasnoyarsk, Russian Federation, 660003
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Krasnoyarsk, Russian Federation, 660022
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Moscow, Russian Federation, 125167
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Moscow, Russian Federation, 125284
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Murmansk, Russian Federation
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Nizhny Novgorod, Russian Federation
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Novosibirsk, Russian Federation
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Petrozavodsk, Russian Federation
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Rostov-na-Donu, Russian Federation
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Saint Petersburg, Russian Federation
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Saratov, Russian Federation
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Ufa, Russian Federation
Singapore
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Singapore, Singapore
Spain
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Barcelona, Spain
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Madrid, Spain
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Majadahonda, Spain
Sweden
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Uppsala, Sweden
Taiwan
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Chang-hua, Taiwan
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Hualien City, Taiwan
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Kaohsiung, Taiwan
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Taichung, Taiwan
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Tainan, Taiwan
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Taipei, Taiwan
Thailand
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Bangkok, Thailand
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Hat Yai, Thailand
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Pathum Wan, Thailand
Turkey
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Eskişehir, Turkey
United Kingdom
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Leeds, United Kingdom
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London, United Kingdom
Sponsors and Collaborators
Alexion Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:
Statistical Analysis Plan  [PDF] December 12, 2017
Study Protocol  [PDF] March 1, 2019

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Alexion Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02946463    
Other Study ID Numbers: ALXN1210-PNH-301
2016-002025-11 ( EudraCT Number )
First Posted: October 27, 2016    Key Record Dates
Results First Posted: February 12, 2019
Last Update Posted: May 15, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Ravulizumab
Hemoglobinuria
Hemoglobinuria, Paroxysmal
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Anemia, Hemolytic
Anemia
Hematologic Diseases
Myelodysplastic Syndromes
Bone Marrow Diseases
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs