TOP: Recombinant Human Parathyroid Hormone (ALX1-11) on Fracture Incidence in Women With Postmenopausal Osteoporosis

Osteoporosis Clinical Trial

Official title:

An 18-Month Double-Blind, Placebo-Controlled, Phase III, Trial With a 12-Month Interim Analysis of the Effect of Recombinant Human Parathyroid Hormone (ALX1-11) on Fracture Incidence in Women With Postmenopausal Osteoporosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00172081
• Other study ID #: ALX1-11-93001
• Status: Completed
• Phase: Phase 3
• Start date: April 27, 2000
• Est. completion date: November 7, 2003

Study information

• Verified date: May 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an 18-month, double-blind, placebo-controlled, Phase III trial with a 12-month interim analysis of the effect of ALX1-11, recombinant human parathyroid hormone (1-84) (rhPTH [1-84]), on fracture incidence in women with postmenopausal osteoporosis, the TOP study.

Description:

Parathyroid hormone (PTH), a polypeptide consisting of 84 amino acids that is synthesized and secreted by the parathyroid glands, is a principal regulator of calcium homeostasis through concerted action on kidney, intestine and bone. Parathyroid hormone exerts its action on bone to release calcium into the extracellular fluid as a process of bone remodeling and also to maintain the serum calcium concentration, but the exact mechanisms are not fully understood. In some circumstances, PTH may exert an anabolic action on bone and can stimulate osteoblast proliferation and mature osteoblast function. The net effect of exogenous PTH administration on bone turnover depends on the pattern of delivery. A continuous long-term infusion gives a net decrease in trabecular bone volume, whereas daily single injections result in a net increase. NPS Allelix Corp. is developing ALX1-11, recombinant human parathyroid hormone (1-84), for the treatment of osteoporosis. ALX1-11 is identical to the endogenous intact 84 amino acid human hormone and will be self-administered on a daily basis by subcutaneous (sc) injection. Currently, there is no approved therapy for osteoporosis capable of stimulating the formation of new bone of normal composition and structure. Most therapies in development are anti-catabolic and only prevent further bone loss (e.g., estrogen replacement, bisphosphonates, and calcitonins). ALX1-11 has the potential to stimulate new bone formation in osteoporotic patients, thereby increasing bone mass and preventing fractures. Patients with moderately or severely reduced bone density and a fracture would be expected to benefit from treatment, thereby improving functional status and alleviating symptoms.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2532
• Est. completion date: November 7, 2003
• Est. primary completion date: November 7, 2003
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 45 Years and older

Eligibility

Inclusion Criteria:

• Women who are postmenopausal with at least one year since the last menstruation.
• Women who are 45-54 years of age with the following bone mineral density (BMD) and/or

vertebral fracture:

• BMD 3.0 standard deviations (SDs) or more below peak bone mass of young females at the lumbar spine, femoral neck, or total hip; or
• BMD 2.5 SDs or more below peak bone mass of young females at the lumbar spine, femoral neck or total hip with the presence of a vertebral fracture verified by the central imaging organization before the patient is enrolled into the study.
• Women 55 or more years of age with the following BMD and/or vertebral fracture:
• BMD 2.5 SDs or more below peak bone mass of young females at the lumbar spine, femoral neck or total hip; or
• BMD 2.0 SDs or more below peak bone mass of young females at the lumbar spine, femoral neck or total hip with the presence of a vertebral fracture verified by the central imaging organization before the patient is enrolled into the study.
• The following types of vertebral fractures should not be considered for patient

enrollment into this trial:

• Pathological fractures due to malignant disease or infection
• Fractures due to excessive trauma sufficient to cause a fracture in young individuals with normal bone mass
• 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 clinical trial screening visit Exclusion Criteria:

A. Vertebral Deformity:

• Patient has 5 or more vertebral (thoracic and lumbar) deformities
• Patient has 2 or more lumbar vertebral deformities (L1 to L4)
• Severe lumbar scoliosis (>15 degrees) which precludes a reliable evaluation of the dual x-ray absorptiometry (DXA)

B. DXA Imaging:

• Inability to have a DXA scan performed.

C. History or Concurrent Illness:

• Disorders of immunity
• Endocrine system
• Gastrointestinal system
• Kidney and collecting system
• Liver, biliary tract and pancreatic systems
• Musculoskeletal system
• Neoplasia
• Nervous system
• Vascular, respiratory and cardiac system
• Significant diseases or disorders are determined by history, physical exam or laboratory screens and judged by the Principal Investigator to be significant. D. Concurrent Medication: Any patient who does not require medication washout (discontinuation) as specified below may start study drug dosing after 2 weeks of stabilization treatment with calcium and vitamin D3 supplements. All exceptions will be documented in the case report form (CRF).
• Patients cannot be enrolled into this clinical trial if they have received any of the

following therapies at any time:

• Any PTH or PTH analogs [e.g., rhPTH(1-84), PTH(1-34), PTHrP and analogs]
• Fluoride
• Strontium
• Patients must have been off the following agents for the specified times before

entering the screening phase of this clinical trial:

• Any investigational drug (30 days)
• Anabolic steroids or androgens (6 consecutive months)
• Active vitamin D3 metabolites and analogs(90 days)
• Systemic corticosteroids, more than 5 mg/day prednisone or a systemic corticosteroid formulation equivalent to 5 mg/day prednisone (12 consecutive months).
• A patient who has been enrolled in the study 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 is limited to no more than 30 consecutive days

2. The maximal dose of steroid (prednisone equivalent) is 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 treatment period of the study

• Daily inhaled corticosteroids unless dose is below 1200 mg/day of beclomethasone.
• Bisphosphonates, including investigational bisphosphonates.
• Intravenous (IV) pamidronate. Patient must be receiving pamidronate specifically to treat osteoporosis. Patient can have received only ONE IV dose of pamidronate in the 12 months immediately preceding the screening visit.
• Cyclical etidronate. Exposure to cyclical etidronate must be less than or equal to 6 months on a standard dose (e.g. 400 mg/day). Patient should not have exposure to cyclical etidronate for 9 months prior to the screening visit.
• Phenytoin for seizure control. If the patient has received phenytoin within five years of the screening visit, the patient is excluded from this study. The patient may continue in the screening process if 15 years have passed since the last dose of phenytoin at the time of the screening visit. If the phenytoin use was between 5-15 years before the screening visit and the patient received phenytoin for less than 2 months.
• Patients may be enrolled 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. * Stable dosage of thiazide for at least 3 consecutive months.
• All patients must stop the following therapies at least 4 weeks prior to the screening visit and remain off these therapies for the remainder of the clinical trial. Screening laboratories must be performed after the washout is complete. However, imaging studies (BMD, X-rays) may be performed prior to starting the calcitonin, estrogen, and selective estrogen receptor modulation (SERM) washout.
• 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 conjugated estrogen or estradiol* Cytostatics, e.g., azathioprine, recombinant human tumor necrosis fusion (Fc) protein, monoclonal antibody against tumor necrosis factor (e.g., remicade [infliximab])
• The drug class tetracyclines
• Medication known to affect the metabolism of bone (the Principal Investigator should discuss this with the Project Medical Officer before the patient is excluded from enrollment)

E. Miscellaneous Concurrent Medications:

• Methotrexate
• Intra-articular injections - Patients with chronic, active joint disease should be excluded from this Phase III study. Patients may receive a maximum of one intra-articular injection (ONE JOINT ONLY) every 6 months while participating in this Phase III study. 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.

F. Laboratory Values and Physical Examination Findings:

• Serum calcium greater than 10.7 mg/dL (2.66 mmol/L). At screening, if the serum calcium is abnormal, the patient may have the additional evaluation described below

ONCE:

1. Discontinue all oral calcium and vitamin D3 supplements.

2. Repeat a fasting serum calcium level two weeks later.

3. If the fasting serum calcium level is still abnormal, the patient is discontinued from the study.

4. If the repeat fasting serum calcium is normal, the patient should have supplemental calcium and vitamin D3 restarted at the time of study drug dosing, without going through a two-week stabilization period.

• Serum creatinine > 1.5 mg/dL (132.6 mmol/L)
• Urinary calcium to creatinine ratio is greater than or equal to 1. At screening, if a patient's urinary calcium to creatinine ratio is abnormal, the patient may have the

additional evaluation described below ONCE:

1. Discontinue all oral calcium and vitamin D3 supplements.

2. Repeat a fasting urine calcium to creatinine ratio two weeks later.

3. If the fasting urinary calcium to creatinine ratio is still abnormal, the patient is discontinued from the study.

4. If the repeat fasting urinary calcium to creatinine ratio is normal, the patient should have supplemental calcium and vitamin D3 restarted at the time of study drug dosing, without going through a two-week stabilization period.

• Total serum alkaline phosphatase >130 U/L except as noted - Argentina (311 U/L); Brazil (278 U/L); Mexico (159 U/L).
• Any other clinically significant abnormal value as judged by the investigator
• Body weight below 40 kg

G. Substance Abuse:

• Alcohol and/or drug abuse

H. Psychiatric Disease:

• Current or history of psychiatric disease that would interfere with the ability to comply with the clinical trial protocol

I. Compliance:

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

Related Conditions & MeSH terms

• Osteoporosis
• Osteoporosis, Postmenopausal

Intervention

Drug:
• placebo
Daily subcutaneous injection with placebo
• ALX1-11
PTH (1-84) 100 mcg injected subcutaneously into the thigh or abdomen

Locations

Country	Name	City	State
Argentina	'Centro Médico T.I.E.M.P.O	Buenos Aires	BUE
Argentina	'Hospital Ramos Mejía	Buenos Aires	BUE
Argentina	'IDIM	Buenos Aires	BUE
Argentina	'Centro de Osteopatias Medicas	Capital Federal	CBA
Brazil	'Hospital Santa Casa de Misericórdia do Rio de Janeiro	'Rio de Janeiro	RJ
Brazil	'Pontifícia Universidade Católica de Campinas	Campinas	SP
Brazil	'UNICAMP	Campinas	SP
Brazil	'Universidade Federal do Paraná	Curitiba	PR
Brazil	'Universidade Federal de Pernambuco	Recife	PE
Brazil	'Hospital do Servidor Público do Rio de Janeiro	Rio de Janeiro	RJ
Brazil	'Hospital Heliópolis	Sao Paulo	SP
Brazil	'Hospital Santa Casa de Misericórdia de São Paulo	Sao Paulo	SP
Brazil	'Instituto de Saúde e Bem Estar da Mulher	Sao Paulo	SP
Brazil	'Universidade Federal de São Paulo	Sao Paulo	SP
Bulgaria	'Multifunctional Hospital for Active Treatment "Sv.Georgy"	Plovdiv
Bulgaria	'Multifunctional Hospital for Active Treatment "Alexandrovska	Sofia
Bulgaria	'Multifunctional Hospital for Active Treatment "Sv.Ivan Rilsky"	Sofia
Bulgaria	'SHATENG"Acad.Ivan Penchev"	Sofia
Bulgaria	'SHATGO"Sheynovo"	Sofia
Canada	'Saskatoon Osteoporosis Centre	'Saskatoon	Saskatchewan
Canada	'Heritage Medical Research Clinic	Calgary	Alberta
Canada	'Riverside Medical Centre	Charlottetown	Prince Edward Island
Canada	'Complexe Hospitalier de la Sagami	Chicoutimi	Quebec
Canada	Charlton Medical Centre	Hamilton	Ontario
Canada	Rafat Faraawi	Kitchener	Ontario
Canada	'Centre for Activity and Aging	London	Ontario
Canada	St. Joseph's Health Centre	London	Ontario
Canada	'Centre d'Etude Clinique Montreal Inc.	Montreal	Quebec
Canada	'Centre de Recherche du CHUM - Hopital Saint-Luc	Montreal	Quebec
Canada	'Hopital Maisonneuve-Rosemont	Montreal	Quebec
Canada	'Royal Victoria Hospital	Montreal	Ontario
Canada	Oakville Bone Center	Oakville	Ontario
Canada	Ottawa Hospital	Ottawa	Ontario
Canada	Centre de Recherche - CORQ	Sainte-Foy	Quebec
Canada	Novabyss Research Clinic	Sherbrooke	Quebec
Canada	'Osteoporosis Research Program	Toronto	Ontario
Canada	'St. Michael's Hospital	Toronto	Ontario
Canada	'Sunnybrook and Women's College Health Science Center	Toronto	Ontario
Canada	Osteoporosis Research Center	Vancouver	British Columbia
Canada	Jude F. Rodrigues	Windsor	Ontario
Canada	'Manitoba Clinic	Winnipeg	Manitoba
Israel	'Clalit Health Services	Beer Sheva
Israel	'Soroka Medical Center	Beer Sheva
Israel	'Hillel Yaffe Medical Center	Hadera
Israel	'Lin Medical Center	Haifa
Israel	'Rambam Medical Center	Haifa
Israel	'Hadassah University Hospital	Jerusalem
Israel	'Rabin Medical Center	Petach Tikva
Israel	'Chaim Sheba Medical Center	Ramat Gan
Israel	'Lis Maternity Hospital	Tel Aviv
Mexico	'Hospital Angeles de las Lomas	'Huixquilucan	Emex
Mexico	'Hospital Central "Ignacio Morones Prieto"	'San Luis Potosi	SLP
Mexico	'Hospital Clinical del Parque	Chihuahua	Chih
Mexico	'Hospital Civil de Belem	Guadalajara	JAL
Mexico	'Medica Monraz	Guadalajara	JAL
Mexico	'OPD Hospital Civil de Guadalajara Dr. Juan I. Menchaca	Guadalajara	JAL
Mexico	'Hospital Aranda de la Parra	Leon	GTO
Mexico	'Hospital de Mexico	Mexico	DF
Mexico	'Instituto Mexicano de Investigacion Clinica	Mexico	DF
Mexico	'Osteosol	Mexico	DF
Mexico	'Hospital Universitario de Monterrey	Monterrey Nuevo Leon
Romania	'Centrul Medical Sabyc	Bucuresti
Romania	'CLINTRIAL "DORIS" Medical Centre	Bucuresti
Romania	'Spitalul Clinic Judetean Cluj-Napoca	Cluj-Napoca
Russian Federation	'JK "Medicine"	Moscow
Russian Federation	'Russian Academy for Advanced Medical Studies	Moscow
Russian Federation	'Scientific Center of Endocrinology of RAMS	Moscow
United States	'Lovelace Scientific Resources	Albuquerque	New Mexico
United States	'New Mexico Clinical Research and Osteoporosis Center	Albuquerque	New Mexico
United States	'Robin K. Dore, M.D., Inc.	Anaheim	California
United States	'Radiant Research	Anderson	South Carolina
United States	'The Emory Clinic	Atlanta	Georgia
United States	'Maine Center for Osteoporosis Research & Education	Bangor	Maine
United States	'Comprehensive Clinical Research	Berlin	New Jersey
United States	'Bethesda Health Research Center	Bethesda	Maryland
United States	'Osteoporosis Medical Center	Beverly Hills	California
United States	'The University of Alabama at Birmingham	Birmingham	Alabama
United States	Capstone Clinical Trials	Birmingham	Alabama
United States	'Odyssey Research Services	Bismarck	North Dakota
United States	'ICSL-Clinical Studies	Bloomington	Illinois
United States	'RASF - Clinical Research Center	Boca Raton	Florida
United States	'Intermountain Orthopaedics	Boise	Idaho
United States	'Brigham & Women's Hospital	Boston	Massachusetts
United States	'Fletcher Allan Health Center, UHC Campus 1	Burlington	Vermont
United States	'Carolina Bone and Joint - Charlotte	Charlotte	North Carolina
United States	'Clinsearch	Chattanooga	Tennessee
United States	'The University of Chicago	Chicago	Illinois
United States	Rush-Prebyterian-St.Luke's Medical Center	Chicago	Illinois
United States	'Cleveland Clinic Foundation	Cleveland	Ohio
United States	'Columbia Arthritis Center, PA	Columbia	South Carolina
United States	'Arthritis, Osteoporosis Muscle Skeletal Disease Center	Concord	New Hampshire
United States	'East Bay Clinical Trial Center	Concord	California
United States	'The Osteoporosis and Clinical Trials Center	Cumberland	Maryland
United States	'Radiant Research/Dallas	Dallas	Texas
United States	'Denver Arthritis Clinic	Denver	Colorado
United States	'Mercy Arthritis and Osteoporosis Center	Des Moines	Iowa
United States	'Michigan Bone & Mineral Clinic	Detroit	Michigan
United States	'Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	'Duke University Medical Center	Durham	North Carolina
United States	'Phase III Clinical Research	Fall River	Massachusetts
United States	Michael J. Lillestol	Fargo	North Dakota
United States	'ICSL Clinical Studies	Fort Myers	Florida
United States	'Arthritis & Osteoporosis Center of Maryland	Frederick	Maryland
United States	'Altru Health Systems/Altru Research Center	Grand Forks	North Dakota
United States	'Radiant Research	Greer	South Carolina
United States	'The Osteoporosis and Clinical Trials Center	Hagerstown	Maryland
United States	'Northeast Clinical Research, LLC	Hamden	Connecticut
United States	'The Center for Diabetes and Endocrine Care	Hollywood	Florida
United States	'Radiant Research	Honolulu	Hawaii
United States	'Breco Research Inc.	Houston	Texas
United States	'Rheumatology Associates of North Alabama	Huntsville	Alabama
United States	'University Hospital & Outpatient Center	Indianapolis	Indiana
United States	'Florida Wellcare Alliance	Inverness	Florida
United States	'Radiant Research - Lake Worth	Lake Worth	Florida
United States	'Colorado Center for Bone Research	Lakewood	Colorado
United States	'VA Southern NV Healthcare Systems	Las Vegas	Nevada
United States	'Loma Linda Osteoporosis Research Center	Loma Linda	California
United States	'Longmont Medical Research Network	Longmont	Colorado
United States	'University of Wisconsin Medical Foundation	Madison	Wisconsin
United States	'David R. Mandel M.D. Inc.	Mayfield	Ohio
United States	'Osteoporosis Center	Medford	Oregon
United States	'Osteoporosis Center University of Miami	Miami	Florida
United States	'Diabetes Center of the Southwest	Midland	Texas
United States	'Medical College of Wisconsin	Milwaukee	Wisconsin
United States	'Bone Mineral Research Center	Mineola	New York
United States	'Odyssey Research Services	Minot	North Dakota
United States	'Ochsner Clinic	New Orleans	Louisiana
United States	'Beth Israël Medical Center	New York	New York
United States	'College of Physicians and Surgeons, Columbia University	New York	New York
United States	'Center for Arthritis and Diabetes	Newport News	Virginia
United States	'The Foundation for Osteoporosis Research and Education	Oakland	California
United States	'Renstar Medical Group	Ocala	Florida
United States	'Desoto Family Medical Center	Olive Branch	Mississippi
United States	'South Puget Sound Clinical Research Center	Olympia	Washington
United States	'Diabetes and Endocrinology Treatment Center	Palm Beach Gardens	Florida
United States	'Desert Medical Advances	Palm Desert	California
United States	'The Arthritis Center	Palm Harbor	Florida
United States	'VA Palo Alto Health Care System	Palo Alto	California
United States	'Thomas Jefferson University	Philadelphia	Pennsylvania
United States	'Radiant Research - Phoenix	Phoenix	Arizona
United States	'University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	'Rhode Island Hospital	Providence	Rhode Island
United States	'Roger Williams Medical Center	Providence	Rhode Island
United States	'Boling Clinical Trials	Rancho Cucamonga	California
United States	'Rapid City Medical Center	Rapid City	South Dakota
United States	'MCV Physicians Program for Osteoporosis	Richmond	Virginia
United States	'National Clinical Research, Inc.	Richmond	Virginia
United States	'Rochester Clinical Research Inc.	Rochester	New York
United States	'ICSL Clinical Studies	Saint Petersburg	Florida
United States	'Diabetes & Glandular Disease Research Associates, P.A.	San Antonio	Texas
United States	'Radiant Research San Antonio	San Antonio	Texas
United States	'Radiant Research - San Diego	San Diego	California
United States	'S.D. Arthritis & Osteoporosis Medical Clinic	San Diego	California
United States	'San Francisco General Hospital	San Francisco	California
United States	'Salt Lake Women's Center	Sandy	Utah
United States	'Community Research Centers	Santa Ana	California
United States	'Osteoporosis Research Group	Seattle	Washington
United States	Phillip J. Mease	Seattle	Washington
United States	'Averna Research Institute	Sioux Falls	South Dakota
United States	'The Centre for Arthritis and Rheumatic Diseases	South Miami	Florida
United States	'Anderson and Collins Clinical Research Inc.	South Plainfield	New Jersey
United States	'St. John's Medical Research Group	Springfield	Missouri
United States	'Stony Brook Clinical Research Trials Center	Stony Brook	New York
United States	'Radiant Research - Stuart & LakeWorth	Stuart	Florida
United States	'Oklahoma Center for Arthritis Therapy & Research, Inc.	Tulsa	Oklahoma
United States	'Georgetown University Medical Center	Washington	District of Columbia
United States	'Brown Clinic	Watertown	South Dakota
United States	'Palm Beach Research Center	West Palm Beach	Florida
United States	'Clinical Research Center of Reading LLP	West Reading	Pennsylvania
United States	'The Center for Rheumatology and Bone Research	Wheaton	Maryland
United States	'Physicians Clinical Research Services	White Plains	New York
United States	'Wichita Clinic	Wichita	Kansas
United States	'Osteoporosis Research & Treatment Center	Worcester	Massachusetts
United States	'Radiant Research	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Shire

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Bulgaria,  Canada,  Israel,  Mexico,  Romania,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Compare effects of 18 months of treatment with ALX1-11/placebo on the incidence of new and/or worsened thoracic and lumbar vertebral fractures in postmenopausal women with osteoporosis receiving calcium and vitamin D3 supplements		At Month 18
Secondary	Incidences of vertebral fractures at Month 12; hip and wrist fractures; and other clinical fractures.		At Month 12