Therapy With Zoledronic Acid in Patients With Multiple Myeloma Stage I

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00171925
• Collaborator: (none)
• Enrollment: 143
• Location: 1
• Arms: 2
• Duration (Months): 99
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Multiple myeloma is a disease of B-lymphocytes producing malignant plasma cells. Malignant plasma cells induce osteolytic lesions, which is characteristic for progression of multiple myeloma. It is the aim of this study to investigate whether zoledronic acid has an influence on the progression of multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma Stage I	Drug: Zoledronic acid; Dietary Supplement: Calcium / Vitamin D	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 143 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Therapy With Zoledronic Acid in Patients With Multiple Myeloma Stage I
• Study Start Date: Aug 1, 2000
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zoledronic acid (ZOL446) Participants received intravenous infusion of Zoledronic acid every 4 weeks for 48 weeks, and calcium and Vitamin D daily.	Drug: Zoledronic acid; Zoledronic acid administered via normal saline intravenous infusion (over 15 minutes) every 4 weeks. Dosage was according to calculated creatinine clearance: patients with baseline creatinine clearance > 60 ml/min received 4 mg; for patients with mild to moderate renal impairment, doses were calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 ml/min, assuming target AUC of 0.66 (mg*hr/l).; Dietary Supplement: Calcium / Vitamin D; Patients on zoledronic acid received 500 mg calcium and 400-500 IU vitamin D combination tablet daily.
No Intervention: Control No treatment with study medication.

Outcome Measures

Primary Outcome Measures

1. Days of Progression Free Survival [48 months]

   Progression-free survival was defined as time from date of randomization to death from any cause or one of the following events: progression to stage II or III according to Salmon & Durie classification skeletal related events (pathologic fracture, initiation of radiotherapy or surgery on bone, spinal cord compression or hypercalcemia) unequivocal progression of osteolytic lesions (at least a 20% increase in the largest diameter of one existing osteolytic lesion which is measured in at least one dimension as 20 mm with conventional techniques), determined radiologically.

Secondary Outcome Measures

1. Number of Patients With Progression by Individual Criteria [48 months]

   Number of patients with progression by individual criteria consisting of Progression of disease overall, Skeletal-related events (including pathological fracture, initiation of radiotherapy or surgery on bone, spinal cord compression or Hypercalcemia), Progression to stage II or III according to Salmon & Durie classification, and unequivocal progression of osteolytic lesion. Patients are counted separately for every type of progression, but only once for Overall Progression.

2. The Number of Participants With the Development of Skeletal Complications [48 months]

   Pathologic fracture: bone fractures that occur spontaneously or from trivial trauma. New vertebral compression fracture defined as a decrease in vertebral height of 25% from baseline Spinal cord compression: the impingement of tumor on the spinal cord confirmed by radiography Bone Radiotherapy: Bone irradiation to palliate painful lesions, treat or prevent pathologic fractures or spinal cord compression Surgery on bone: surgical procedures performed to set, stabilize or prevent pathologic fractures or areas of spinal cord compression Hypercalcemia: Corrected serum calcium ≥ 12.0 mg/dl

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Evidence of myeloma according to the criteria of the British Columbia Cancer Agency (for the diagnosis, 2 of the 3 criteria must be met):

• Evidence of paraprotein in the serum or urine

• Bone marrow infiltration with plasma cells which represent more than 10% of the nucleated cells

• Radiologically, at least one osteolytic lesion

• Asymptomatic patients with Stage I (Durie and Salmon) multiple myeloma

Exclusion criteria:

• Patients with more than one osteolytic lesion on conventional skeletal radiography

• Previous treatment with bisphosphonates

• bilirubin > 2.5 mg/dl

• Abnormal renal function as evidenced by: A calculated creatinine clearance < 30 ml/minute. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula:

• CrCl= [140-age(years)] x weight(kg)/[72xserumcreatinine(mg/dL)] X {0.85 for female patients}

• Patients with other malignant diseases or severe concomitant diseases

• Potentially fertile patients who are not using a reliable and appropriate method of contraception

• Pregnancy or breast-feeding

• Participation in another clinical study with an investigational drug within 12 weeks of study entry

• Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.

• Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants)

Other protocol-defined inclusion and exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Berlin		Germany

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00171925
• Other Study ID Numbers: CZOL446 DE01
• First Posted: Sep 15, 2005
• Last Update Posted: Apr 11, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by Novartis Pharmaceuticals: Multiple Myeloma; Stage I; Zoledronic acid; Progression
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Vitamin D; Zoledronic Acid; Calcium

Study Results

Participant Flow

Arm/Group Title	Zoledronic Acid (ZOL446)	Control
Arm/Group Description	Participants received intravenous infusion of Zoledronic acid every 4 weeks for 48 weeks, and calcium and Vitamin D daily.	No Treatment with study medication.
Period Title: Overall Study
STARTED	72	71
COMPLETED	42	40
NOT COMPLETED	30	31

Baseline Characteristics

Arm/Group Title	Zoledronic Acid (ZOL446)	Control	Total
Arm/Group Description	Participants received intravenous infusion of Zoledronic acid every 4 weeks for 48 weeks, and calcium and Vitamin D daily.	No Treatment with study medication.	Total of all reporting groups
Overall Participants	72	71	143
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.8 (12.02)	62.1 (10.79)	60.4 (11.5)
Sex: Female, Male (Count of Participants)
Female	42 58.3%	31 43.7%	73 51%
Male	30 41.7%	40 56.3%	70 49%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	69 95.8%	70 98.6%	139 97.2%
Oriental	2 2.8%	0 0%	2 1.4%
Other	1 1.4%	1 1.4%	2 1.4%
Region of Enrollment (participants) [Number]
Germany	72 100%	71 100%	143 100%

Outcome Measures

1. Primary Outcome

Title	Days of Progression Free Survival
Description	Progression-free survival was defined as time from date of randomization to death from any cause or one of the following events: progression to stage II or III according to Salmon & Durie classification skeletal related events (pathologic fracture, initiation of radiotherapy or surgery on bone, spinal cord compression or hypercalcemia) unequivocal progression of osteolytic lesions (at least a 20% increase in the largest diameter of one existing osteolytic lesion which is measured in at least one dimension as 20 mm with conventional techniques), determined radiologically.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Intent to Treat Population

Arm/Group Title	Zoledronic Acid (ZOL446)	Control
Arm/Group Description	Participants received intravenous infusion of Zoledronic acid every 4 weeks for 48 weeks, and calcium and Vitamin D daily.	No Treatment with study medication.
Measure Participants	71	69
Mean (Standard Error) [Days]	1078.1 (59.53)	992.80 (61.83)

2. Secondary Outcome

Title	Number of Patients With Progression by Individual Criteria
Description	Number of patients with progression by individual criteria consisting of Progression of disease overall, Skeletal-related events (including pathological fracture, initiation of radiotherapy or surgery on bone, spinal cord compression or Hypercalcemia), Progression to stage II or III according to Salmon & Durie classification, and unequivocal progression of osteolytic lesion. Patients are counted separately for every type of progression, but only once for Overall Progression.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Intent to Treat Population

Arm/Group Title	Zoledronic Acid (ZOL446)	Control
Arm/Group Description	Participants received intravenous infusion of Zoledronic acid every 4 weeks for 48 weeks, and calcium and Vitamin D daily.	No Treatment with study medication.
Measure Participants	71	69
Progression of disease overall	19 26.4%	26 36.6%
Skeletal-related events	0 0%	4 5.6%
Progression to stage II or III	17 23.6%	24 33.8%
Unequivocal progression of osteolytic lesion	3 4.2%	10 14.1%

3. Secondary Outcome

Title	The Number of Participants With the Development of Skeletal Complications
Description	Pathologic fracture: bone fractures that occur spontaneously or from trivial trauma. New vertebral compression fracture defined as a decrease in vertebral height of 25% from baseline Spinal cord compression: the impingement of tumor on the spinal cord confirmed by radiography Bone Radiotherapy: Bone irradiation to palliate painful lesions, treat or prevent pathologic fractures or spinal cord compression Surgery on bone: surgical procedures performed to set, stabilize or prevent pathologic fractures or areas of spinal cord compression Hypercalcemia: Corrected serum calcium ≥ 12.0 mg/dl
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Zoledronic Acid (ZOL446)	Control
Arm/Group Description	Participants received intravenous infusion of Zoledronic acid every 4 weeks for 48 weeks, and calcium and Vitamin D daily.	No Treatment with study medication.
Measure Participants	71	69
Skeletal events overall	0 0%	4 5.6%
Pathological fracture	0 0%	1 1.4%
Initiation of radiotherapy or surgery on bone	0 0%	1 1.4%
Spinal cord compression	0 0%	2 2.8%
Hypercalcemia	0 0%	0 0%

Adverse Events

Arm/Group Title	Zoledronic Acid		Control
Arm/Group Description	Participants received intravenous infusion of Zoledronic acid every 4 weeks for 48 weeks, and calcium and Vitamin D daily.		No treatment with study medication.
All Cause Mortality
	Zoledronic Acid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zoledronic Acid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/72 (38.9%)		12/71 (16.9%)
Blood and lymphatic system disorders
Anaemia	1/72 (1.4%)		1/71 (1.4%)
Cardiac disorders
Aortic valve disease	1/72 (1.4%)		0/71 (0%)
Arrhythmia	1/72 (1.4%)		0/71 (0%)
Cardiac amyloidosis	1/72 (1.4%)		0/71 (0%)
Cardiac disorder	0/72 (0%)		1/71 (1.4%)
Left ventricular failure	1/72 (1.4%)		0/71 (0%)
Congenital, familial and genetic disorders
Phimosis	1/72 (1.4%)		0/71 (0%)
Endocrine disorders
Goitre	1/72 (1.4%)		0/71 (0%)
Toxic nodular goitre	1/72 (1.4%)		0/71 (0%)
Gastrointestinal disorders
Abdominal pain	1/72 (1.4%)		0/71 (0%)
Ileus	0/72 (0%)		1/71 (1.4%)
General disorders
Condition aggravated	1/72 (1.4%)		0/71 (0%)
Death	0/72 (0%)		1/71 (1.4%)
Multi-organ failure	0/72 (0%)		1/71 (1.4%)
Oedema	1/72 (1.4%)		0/71 (0%)
Pyrexia	2/72 (2.8%)		0/71 (0%)
Hepatobiliary disorders
Cholecystitis	1/72 (1.4%)		0/71 (0%)
Cholelithiasis	1/72 (1.4%)		1/71 (1.4%)
Infections and infestations
Erysipelas	1/72 (1.4%)		0/71 (0%)
Haematoma infection	1/72 (1.4%)		0/71 (0%)
Herpes zoster	1/72 (1.4%)		0/71 (0%)
Pneumonia	1/72 (1.4%)		1/71 (1.4%)
Sepsis	0/72 (0%)		1/71 (1.4%)
Injury, poisoning and procedural complications
Clavicle fracture	1/72 (1.4%)		0/71 (0%)
Facial bones fracture	1/72 (1.4%)		0/71 (0%)
Foot fracture	1/72 (1.4%)		0/71 (0%)
Head injury	1/72 (1.4%)		0/71 (0%)
Humerus fracture	0/72 (0%)		1/71 (1.4%)
Jaw fracture	1/72 (1.4%)		0/71 (0%)
Joint injury	2/72 (2.8%)		0/71 (0%)
Ligament rupture	1/72 (1.4%)		0/71 (0%)
Lumbar vertebral fracture	2/72 (2.8%)		0/71 (0%)
Open wound	1/72 (1.4%)		0/71 (0%)
Rib fracture	1/72 (1.4%)		0/71 (0%)
Tooth fracture	1/72 (1.4%)		0/71 (0%)
Traumatic brain injury	1/72 (1.4%)		0/71 (0%)
Wound	1/72 (1.4%)		0/71 (0%)
Investigations
Blood glucose increased	1/72 (1.4%)		0/71 (0%)
Haemoglobin decreased	1/72 (1.4%)		0/71 (0%)
Metabolism and nutrition disorders
Dehydration	0/72 (0%)		1/71 (1.4%)
Hypercalcaemia	1/72 (1.4%)		1/71 (1.4%)
Musculoskeletal and connective tissue disorders
Arthritis	0/72 (0%)		1/71 (1.4%)
Arthritis reactive	1/72 (1.4%)		0/71 (0%)
Intervertebral disc disorder	1/72 (1.4%)		0/71 (0%)
Osteoarthritis	3/72 (4.2%)		0/71 (0%)
Osteonecrosis of the jaw	4/72 (5.6%)		0/71 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer	1/72 (1.4%)		0/71 (0%)
Meningioma	0/72 (0%)		1/71 (1.4%)
Multiple myeloma	0/72 (0%)		1/71 (1.4%)
Papilloma	1/72 (1.4%)		0/71 (0%)
Small cell lung cancer stage unspecified	0/72 (0%)		1/71 (1.4%)
Nervous system disorders
Dizziness	1/72 (1.4%)		0/71 (0%)
Polyneuropathy	2/72 (2.8%)		0/71 (0%)
Radicular syndrome	1/72 (1.4%)		0/71 (0%)
Spinal cord compression	0/72 (0%)		1/71 (1.4%)
Stupor	0/72 (0%)		1/71 (1.4%)
Syncope	1/72 (1.4%)		0/71 (0%)
Psychiatric disorders
Alcohol withdrawal syndrome	0/72 (0%)		1/71 (1.4%)
Depression	0/72 (0%)		1/71 (1.4%)
Renal and urinary disorders
Renal failure	1/72 (1.4%)		0/71 (0%)
Urinary retention	1/72 (1.4%)		0/71 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/72 (1.4%)		0/71 (0%)
Menorrhagia	0/72 (0%)		1/71 (1.4%)
Uterine malposition	1/72 (1.4%)		0/71 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchitis chronic	1/72 (1.4%)		0/71 (0%)
Dyspnoea	1/72 (1.4%)		0/71 (0%)
Skin and subcutaneous tissue disorders
Pruritus	0/72 (0%)		1/71 (1.4%)
Vascular disorders
Deep vein thrombosis	1/72 (1.4%)		0/71 (0%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/72 (84.7%)		51/71 (71.8%)
Ear and labyrinth disorders
Vertigo	4/72 (5.6%)		4/71 (5.6%)
Gastrointestinal disorders
Constipation	5/72 (6.9%)		0/71 (0%)
Diarrhoea	6/72 (8.3%)		3/71 (4.2%)
Nausea	6/72 (8.3%)		2/71 (2.8%)
General disorders
Chills	5/72 (6.9%)		0/71 (0%)
Fatigue	7/72 (9.7%)		3/71 (4.2%)
Influenza like illness	7/72 (9.7%)		0/71 (0%)
Oedema peripheral	4/72 (5.6%)		3/71 (4.2%)
Pain	5/72 (6.9%)		4/71 (5.6%)
Pyrexia	11/72 (15.3%)		0/71 (0%)
Infections and infestations
Bronchitis	7/72 (9.7%)		4/71 (5.6%)
Infection	4/72 (5.6%)		1/71 (1.4%)
Nasopharyngitis	24/72 (33.3%)		10/71 (14.1%)
Respiratory tract infection	4/72 (5.6%)		3/71 (4.2%)
Sinusitis	3/72 (4.2%)		5/71 (7%)
Urinary tract infection	4/72 (5.6%)		1/71 (1.4%)
Investigations
Blood creatinine increased	5/72 (6.9%)		2/71 (2.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	17/72 (23.6%)		9/71 (12.7%)
Back pain	15/72 (20.8%)		13/71 (18.3%)
Bone pain	21/72 (29.2%)		4/71 (5.6%)
Musculoskeletal pain	5/72 (6.9%)		4/71 (5.6%)
Osteoarthritis	6/72 (8.3%)		4/71 (5.6%)
Pain in extremity	9/72 (12.5%)		7/71 (9.9%)
Nervous system disorders
Headache	11/72 (15.3%)		5/71 (7%)
Psychiatric disorders
Depression	2/72 (2.8%)		4/71 (5.6%)
Respiratory, thoracic and mediastinal disorders
Cough	4/72 (5.6%)		2/71 (2.8%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	7/72 (9.7%)		1/71 (1.4%)
Night sweats	4/72 (5.6%)		2/71 (2.8%)
Vascular disorders
Hypertension	6/72 (8.3%)		2/71 (2.8%)

Limitations/Caveats

Only exploratory analyses were performed as the trial was terminated early due to lack of obtaining the required sample size. Secondary Outcomes for Quality of Life and Bone Markers not posted due to sparse data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.