Clinical trial NCT00172133: Open Label Extension Study of PREOS
Official title: An 18-Month Open Label Extension Study (OLES) of the Safety and Efficacy of Recombinant Human Parathyroid Hormone, rhPTH(1-84), ALX1-11, in Women With Postmenopausal Osteoporosis Who Participated in Protocol ALX1-11-93001 (TOP Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Osteoporosis
Keywords: Post-menopausal
Osteoporosis
Parathyroid Hormone
PTH
ALX1-11
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2005-09-15
Enrollment: 1683
Sex: FEMALE
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an Open Label Extension Study (OLES) for patients who participated in the 18 month double-blind, placebo-controlled, Phase III trial (Protocol ALX1 11 93001 the TOP Study) studying the effect of ALX1-11, recombinant human parathyroid hormone, rhPTH(1-84), on vertebral fracture incidence. The primary objective of this study is to evaluate the safety of continued dosing with ALX1-11, up to a maximum of 24 months, in postmenopausal osteoporotic women who participated in Protocol ALX1 11 93001.

Detailed description: Effects of ALX1-11 on bone mineral density (BMD) have been documented in a dose-finding Phase II clinical trial in osteoporotic postmenopausal women, supplemented with calcium and Vitamin D3 but without any other treatment for osteoporosis. The anabolic effects of ALX1-11 in the lumbar vertebrae were statistically significant after the 12-month treatment period and more pronounced than any approved therapy. Additionally, animal studies have shown that the new bone formed by treatment with ALX1 11 is of good quality both histologically and biomechanically.

The primary objective of this OLES is to evaluate the safety of continued dosing with ALX1-11, up to a maximum of 24 months, in postmenopausal osteoporotic women who participated in Protocol ALX1-11-93001. A secondary objective is to assess the change in vertebral BMD and compare the changes observed in patients who received ALX1-11 or placebo in Protocol ALX1-11-93001.

Patients will receive 100 µg/day of ALX1-11 daily via subcutaneous injection in this study. Patients should continue the study drug dosing frequency they were following at the end of Protocol ALX1-11-93001.

To enhance their safety, all patients will continue to take their daily supplements of 700 mg calcium and 400 IU Vitamin D3 prior to and during this OLES. Patients whose calcium supplement was discontinued during Protocol ALX1-11-93001 should maintain that discontinuation during this OLES. However upon completion of ALX1-11 dosing in the OLES, oral calcium supplement at a dose of 700 mg each morning should be restarted and maintained for the remainder of the OLES. Additional supplemental calcium and/or Vitamin D3 will not be permitted. A daily multivitamin supplement may be taken during the study. However, the multivitamin must contain no more than 200 mg/day calcium and 400 IU/day Vitamin D3. Patients will be monitored for the development of hypercalcemia and/or hypercalciuria and managed as described in Appendices 4 and 5.

There will be a stopping rule in this OLES. Any patient who reaches a BMD T score of -0.5 or above, at the site or sites (vertebral, total hip, or femoral neck) that were used in the qualification of the patient for Protocol ALX1 11-93001, will stop ALX1-11 treatment. The patient must continue on calcium and Vitamin D3 and be followed for the remainder of this 18-month OLES. At the time of discontinuation, the patient must complete the Month 18 evaluations (Appendix 1A or 1B).

The Clinical Advisory Board (CAB) used in Protocol ALX1-11-93001 will be involved in reviewing any patient issues that arise in this OLES. This group will provide not only continuity of care for all the patients, but also enhanced and consistent safety monitoring for patients participating in the OLES.

Eligibility criteria: Inclusion Criteria:

* Women who completed 18 months of treatment in Protocol ALX1-11-93001; or
* Women prematurely discontinued from Protocol ALX1-11-93001 who want to participate in OLES for the events listed below must have their clinical course reviewed and approved by the CAB for enrollment into the OLES:

  * Clinical or incident lumbar vertebral fractures as assessed by the central imaging organization
  * Clinical or incident hip fracture
  * Confirmed bone loss at A/P lumbar vertebra or total hip or femoral neck as assessed by the central imaging organization
* Body weight below 40 kg
* Development of an exclusion criterion in Protocol ALX1-11-93001
* It must be accepted by patients whose clinical courses are reviewed by the CAB that participation in OLES may require additional tests at baseline and/or during the study to ensure their utmost safety.
* Women with the ability to self-administer a daily injection or have a designee who will give the injections;
* Women who are capable of understanding and giving written, voluntary informed consent before the start of open-label dosing with ALX1-11.

Exclusion Criteria:

A. History or Concurrent Illness:

Disorders of Immunity Endocrine system Gastrointestinal system Kidney and collecting system Liver, biliary tract and pancreatic systems Musculoskeletal system

* Patients with chronic, active joint disease requiring more than one intra-articular injection every 6 months Neoplasia
* Patients who have had squamous or basal cell carcinoma of the skin may enter this study if:

  1. The lesion(s) were fully resected with clear margins described in a written report by a pathologist, and
  2. The patient has had no recurrence of lesions for at least one year from the time of the original resection.

     Nervous system Vascular, respiratory and cardiac system \*Significant diseases or disorders are determined by history, physical exam or laboratory tests and judged by the Principal Investigator to be significant.

     B. Concurrent Medication:

     Patients may not use any of the following therapies while they are enrolled in this OLES without permission from the Sponsor and the PMO:
     * Tetracycline antibiotics for four weeks prior to bone biopsy
     * Any PTH analogs \[e.g., rhPTH(1-84), PTH(1-34), PTHrP and analogs\]
     * Fluoride
     * Strontium
     * Phenytoin for seizure control
     * Any investigational drug other than ALX1-11
     * Anabolic steroids or androgens
     * Active Vitamin D3 metabolites and analogs, e.g., calcitriol
     * Systemic corticosteroids, more than 5 mg/day prednisone or a systemic corticosteroid formulation equivalent to 5 mg/day prednisone

  1. A patient who has been enrolled into the OLES and needs to receive an acute bolus of steroids (oral or injectable) for a self-limited illness may continue treatment in the study if the following requirements are met:
  1. Exposure to steroids will be limited to no more than 30 consecutive days
  2. The maximal dose of steroid (prednisone equivalent) must be limited to no more than 225 mg (7.5 mg each day for 30 days)
  3. The illness is acute in nature and is not expected to recur during the remaining period of the study

     * Bisphosphonates, including investigational bisphosphonates
     * Calcitonin
     * Estrogen replacement therapy by oral, transdermal or intramuscular administration
     * SERM drugs, e.g., tamoxifen, raloxifene, Evista
     * Vaginal application of estrogen-containing creams unless the dose is:

       1. conjugated estrogen or estradiol: maximum of 0.5 g twice each week (total of 1.0 g weekly)
       2. Estrace (Ogen): maximum of 1.0 g twice each week (total of 2.0 g weekly)
     * Daily inhaled corticosteroid unless dose is equivalent to \<1200 µg/day of beclomethasone
     * Cytostatics, e.g., azathioprine, recombinant human tumor necrosis fusion (Fc) protein, monoclonal antibody against tumor necrosis factor (e.g., remicade \[infliximab\]
     * Methotrexate

       1. The antimetabolite, methotrexate, which interferes with DNA synthesis, repair and cellular replication should not be used by patients participating in this OLES.
     * In general, immunomodulatory agents with antiproliferative activity are not permitted as a concomitant medication in this OLES.
     * Intra-articular injections

       1. Patients may receive a maximum of one intra-articular injection (ONE JOINT ONLY) every 6 months while participating in this OLES. The joint that is injected may be a different joint every 6 months. The dose of corticosteroid injected should not exceed the anti-inflammatory equivalent dose of Prednisone 40 mg suspension. The dose and volume should be adjusted downward as appropriate to the size of the joint.
     * Provera is an acceptable concomitant medication when used according to the label instructions

     Patients may be enrolled in this OLES if they have been stabilized on the following therapy for the specified amount of time:
     * Thyroid Hormone (\<0.1 mg/day thyroxine) therapy for at least 6 months If taking \> 0.1 mg/day but \< 0.2 mg/day, must have serum TSH level 1. \> 0.1mU/L. Patients will be excluded if they are taking doses of \> 0.2 mg/day.

       2. However, if a patient has had a minimal change in L-thyroxine dose of \< 0.025 mg/day within 6 months of the baseline visit, and has been on this new dose for at least 2 months, the patient may be enrolled in this study. The patient's history with L-thyroxine must be clearly documented in the source documents.

       3. If a patient requires an increase in their thyroid replacement dose, as recommended by a physician who is caring for the patient, after enrollment in this OLES, the patient must have a TSH and T4 level within 3 months of the dose change to ensure the patient does not become hyperthyroid
     * Stable dosage of thiazide for at least 3 consecutive months

     C. Laboratory Values and Physical Examination Findings:

     - Serum calcium greater than 10.7 mg/dL (2.66 mmol/L) at baseline will be managed as outlined in Appendix 4

     - Urinary calcium to creatinine ratio greater than or equal to 1 at baseline will be managed as outlined in Appendix 5
     * Elevated total serum alkaline phosphates (\> 400 U/L) at baseline will be managed as outlined in Appendix 6 except as noted for Latin and South American countries.
     * Any other clinically significant abnormal value as judged by the investigator

     D. Substance Abuse:

     Alcohol and/or drug abuse

     E. Compliance:

     Suspected or confirmed poor compliance in completing clinical trial evaluations and/or clinical trial required questionnaires

Primary outcomes:
measure: To evaluate the safety of continued dosing with ALX1-11, up to a maximum of 24 months, in postmenopausal osteoporotic women who participated in Protocol ALX1-11-93001 (TOP).
timeFrame: 24 months of treatment
Secondary outcomes:
measure: To evaluate the continued efficacy of once-daily treatment with ALX1-11 for maintaining increases in BMD and other measures of bone quality and strength.
timeFrame: 24 months of treatment
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 'The University of Alabama at Birmingham
state: Alabama
city: Huntsville
country: United States
facility: 'Rheumatology Associates of North Alabama
state: Alabama
city: Phoenix
country: United States
facility: 'Radiant Research - Phoenix North
state: Arizona
city: Beverly Hills
country: United States
facility: 'Osteoporosis Medical Center
state: California
city: Concord
country: United States
facility: 'East Bay Clinical Trial Center
state: California
city: Loma Linda
country: United States
facility: 'Loma Linda Osteoporosis Research Center
state: California
city: Oakland
country: United States
facility: Foundation for Osteoporosis Research
state: California
city: Palm Desert
country: United States
facility: 'Desert Medical Advances
state: California
city: Palo Alto
country: United States
facility: 'VA Palo Alto Health Care System
state: California
city: Rancho Cucamonga
country: United States
facility: 'Boling Clinical Trials
state: California
city: San Diego
country: United States
facility: 'S.D. Arthritis & Osteoporosis Medical Clinic
state: California
city: San Diego
country: United States
facility: 'Radiant Research - San Diego
state: California
city: San Francisco
country: United States
facility: 'San Francisco General Hospital
state: California
city: Longmont
country: United States
facility: 'Longmont Medical Research Network
state: Colorado
city: Hamden
country: United States
facility: 'Northeast Clinical Research, LLC
state: Connecticut
city: Boca Raton
country: United States
facility: 'RASF - Clinical Research Center
state: Florida
city: Hollywood
country: United States
facility: 'The Center for Diabetes and Endocrine Care
state: Florida
city: Inverness
country: United States
facility: 'Florida Wellcare Alliance
state: Florida
city: Ocala
country: United States
facility: 'Renstar Medical Group
state: Florida
city: Palm Harbor
country: United States
facility: 'The Arthritis Center
state: Florida
city: South Miami
country: United States
facility: 'The Centre for Arthritis and Rheumatic Diseases
state: Florida
city: Stuart
country: United States
facility: 'Radiant Research - Stuart & LakeWorth
state: Florida
city: West Palm Beach
country: United States
facility: 'Palm Beach Research Center
state: Florida
city: Honolulu
country: United States
facility: 'Radiant Research
state: Hawaii
city: Boise
country: United States
facility: 'Intermountain Orthopaedics
state: Idaho
city: Chicago
country: United States
facility: Rush-Prebyterian-St.Luke's Medical Center
state: Illinois
city: Chicago
country: United States
facility: 'The University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: 'University Hospital & Outpatient Center
state: Indiana
city: Des Moines
country: United States
facility: 'Mercy Arthritis and Osteoporosis Center
state: Iowa
city: Wichita
country: United States
facility: 'Wichita Clinic
state: Kansas
city: New Orleans
country: United States
facility: 'Ochsner Clinic
state: Louisiana
city: Bangor
country: United States
facility: 'Maine Center for Osteoporosis Research & Education
state: Maine
city: Bethesda
country: United States
facility: 'Bethesda Health Research Center
state: Maryland
city: Cumberland
country: United States
facility: 'The Osteoporosis and Clinical Trials Center
state: Maryland
city: Frederick
country: United States
facility: 'Arthritis & Osteoporosis Center of Maryland
state: Maryland
city: Wheaton
country: United States
facility: 'The Center for Rheumatology and Bone Research
state: Maryland
city: Boston
country: United States
facility: 'Brigham & Women's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: 'Michigan Bone & Mineral Clinic
state: Michigan
city: Olive Branch
country: United States
facility: 'Desoto Family Medical Center
state: Mississippi
city: Springfield
country: United States
facility: 'St. John's Medical Research Group
state: Missouri
city: Concord
country: United States
facility: 'Arthritis, Osteoporosis Muscle Skeletal Disease Center
state: New Hampshire
city: South Plainfield
country: United States
facility: 'Anderson and Collins Clinical Research Inc.
state: New Jersey
city: Albuquerque
country: United States
facility: 'New Mexico Clinical Research and Osteoporosis Center
state: New Mexico
city: Albuquerque
country: United States
facility: 'Lovelace Scientific Resources
state: New Mexico
city: New York
country: United States
facility: 'College of Physicians and Surgeons, Columbia University
state: New York
city: Rochester
country: United States
facility: 'Rochester Clinical Research Inc.
state: New York
city: Stony Brook
country: United States
facility: 'Stony Brook Clinical Research Trials Center
state: New York
city: White Plains
country: United States
facility: 'Physicians Clinical Research Services
state: New York
city: Durham
country: United States
facility: 'Duke University Medical Center
state: North Carolina
city: Bismarck
country: United States
facility: 'Odyssey Research Services
state: North Dakota
city: Fargo
country: United States
facility: Michael J. Lillestol
state: North Dakota
city: Grand Forks
country: United States
facility: 'Altru Health Systems / Altru Research Center
state: North Dakota
city: Minot
country: United States
facility: 'Odyssey Research Services
state: North Dakota
city: Cleveland
country: United States
facility: 'Cleveland Clinic Foundation
state: Ohio
city: Mayfield
country: United States
facility: 'David R. Mandel M.D. Inc.
state: Ohio
city: Tulsa
country: United States
facility: 'Oklahoma Center for Arthritis Therapy & Research, Inc.
state: Oklahoma
city: Medford
country: United States
facility: 'Osteoporosis Center
state: Oregon
city: Duncansville
country: United States
facility: 'Altoona Center for Clinical Research
state: Pennsylvania
city: Philadelphia
country: United States
facility: 'Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: 'University of Pittsburgh Medical Center
state: Pennsylvania
city: West Reading
country: United States
facility: 'Clinical Research Center of Reading LLP
state: Pennsylvania
city: Wyomissing
country: United States
facility: 'Radiant Research
state: Pennsylvania
city: Providence
country: United States
facility: 'Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: 'Roger Williams Medical Center
state: Rhode Island
city: Anderson
country: United States
facility: 'Radiant Research
state: South Carolina
city: Columbia
country: United States
facility: 'Columbia Arthritis Center, PA
state: South Carolina
city: Greer
country: United States
facility: 'Radiant Research
state: South Carolina
city: Rapid City
country: United States
facility: 'Rapid City Medical Center
state: South Dakota
city: Sioux Falls
country: United States
facility: 'Averna Research Institute
state: South Dakota
city: Watertown
country: United States
facility: 'Brown Clinic
state: South Dakota
city: Chattanooga
country: United States
facility: 'Clinsearch
state: Tennessee
city: Dallas
country: United States
facility: 'Radiant Research/Dallas
state: Texas
city: Houston
country: United States
facility: 'Breco Research Inc.
state: Texas
city: Midland
country: United States
facility: 'Diabetes Center of the Southwest
state: Texas
city: San Antonio
country: United States
facility: 'Diabetes & Glandular Disease Research Associates, P.A.
state: Texas
city: San Antonio
country: United States
facility: 'Radiant Research San Antonio
state: Texas
city: Sandy
country: United States
facility: 'Salt Lake Women's Center
state: Utah
city: Burlington
country: United States
facility: 'Fletcher Allan Health Center, UHC Campus 1
state: Vermont
city: Newport News
country: United States
facility: 'Center for Arthritis and Diabetes
state: Virginia
city: Richmond
country: United States
facility: 'National Clinical Research, Inc.
state: Virginia
city: Richmond
country: United States
facility: 'MCV Physicians Program for Osteoporosis
state: Virginia
city: Seattle
country: United States
facility: 'Osteoporosis Research Group
state: Washington
city: Madison
country: United States
facility: 'University of Wisconsin Medical Foundation
state: Wisconsin
city: Milwaukee
country: United States
facility: 'Medical College of Wisconsin
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: 'IDIM
state: BUE
city: Buenos Aires
country: Argentina
facility: 'Centro Médico T.I.E.M.P.O
state: BUE
city: Buenos Aires
country: Argentina
facility: 'Hospital Ramos Mejía
state: BUE
city: Capital Federal
country: Argentina
facility: 'Centro de Osteopatias Medicas
state: CBA
city: Curitiba
country: Brazil
facility: 'Universidade Federal do Paraná
state: PR
city: 'Rio de Janeiro
country: Brazil
facility: 'Hospital Santa Casa de Misericórdia do Rio de Janeiro
state: RJ
city: Rio de Janeiro
country: Brazil
facility: 'Hospital do Servidor Público do Rio de Janeiro
state: RJ
city: Sao Paulo
country: Brazil
facility: 'Universidade Federal de São Paulo
state: SP
city: Sao Paulo
country: Brazil
facility: 'Instituto de Saúde e Bem Estar da Mulher
state: SP
city: Sao Paulo
country: Brazil
facility: 'Hospital Heliópolis
state: SP
city: Calgary
country: Canada
facility: 'Heritage Medical Research Clinic
state: Alberta
city: Vancouver
country: Canada
facility: Osteoporosis Research Center
state: British Columbia
city: Winnipeg
country: Canada
facility: 'Manitoba Clinic
state: Manitoba
city: Hamilton
country: Canada
facility: Charlton medical Centre
state: Ontario
city: Kitchener
country: Canada
facility: Rafat Faraawi
state: Ontario
city: London
country: Canada
facility: 'Centre for Activity and Aging
state: Ontario
city: London
country: Canada
facility: St. Joseph's Health Centre
state: Ontario
city: Montreal
country: Canada
facility: 'Royal Victoria Hospital
state: Ontario
city: Oakville
country: Canada
facility: Oakville Bone Center
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: 'Sunnybrook and Women's College Health Science Center
state: Ontario
city: Toronto
country: Canada
facility: 'St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: 'Osteoporosis Research Program
state: Ontario
city: Windsor
country: Canada
facility: Jude F. Rodrigues
state: Ontario
city: Charlottetown
country: Canada
facility: 'Riverside Medical Centre
state: Prince Edward Island
city: Chicoutimi
country: Canada
facility: 'Complexe Hospitalier de la Sagami
state: Quebec
city: Montreal
country: Canada
facility: 'Hopital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: 'Centre de Recherche du CHUM - Hopital Saint-Luc
state: Quebec
city: Sainte-Foy
country: Canada
facility: Centre de recherche - CORQ
state: Quebec
city: Sherbrooke
country: Canada
facility: Novabyss Research Clinic
state: Quebec
city: 'Saskatoon
country: Canada
facility: 'Saskatoon Osteoporosis Centre
state: Saskatchewan
city: Beer Sheva
country: Israel
facility: 'Soroka Medical Center
city: Haifa
country: Israel
facility: 'Rambam Medical Center
city: Haifa
country: Israel
facility: 'Lin Medical Center
city: Jerusalem
country: Israel
facility: 'Hadassah University Hospital
city: Ramat Gan
country: Israel
facility: 'Chaim Sheba Medical Center
city: Tel Aviv
country: Israel
facility: 'Lis Maternity Hospital
city: Mexico
country: Mexico
facility: 'Instituto Mexicano de Investigacion Clinica
state: DF
city: Mexico
country: Mexico
facility: 'Hospital de Mexico
state: DF
city: 'Huixquilucan
country: Mexico
facility: 'Hospital Angeles de las Lomas
state: Emex
city: Leon
country: Mexico
facility: 'Hospital Aranda de la Parra
state: GTO
city: Guadalajara
country: Mexico
facility: 'OPD Hospital Civil de Guadalajara Dr. Juan I. Menchaca
state: JAL
city: Guadalajara
country: Mexico
facility: 'Hospital Civil de Belem
state: JAL
city: Guadalajara
country: Mexico
facility: 'Medica Monraz
state: JAL
city: Monterrey Nuevo Leon
country: Mexico
facility: 'Hospital Universitario de Monterrey
city: Cluj-Napoca
country: Romania
facility: 'Spitalul Clinic Judetean Cluj-Napoca
city: Moscow
country: Russian Federation
facility: 'Scientific Center of Endocrinology of RAMS
city: Moscow
country: Russian Federation
facility: 'Russian Academy for Advanced Medical Studies
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: