NABT;NABT-B: Nitrates and Bone Turnover; Nitrates and Bone Turnover Bisphosphonate Sub-Study

• Sponsor: University of Toronto (Other)
• Overall Status: Completed
• CT.gov ID: NCT01387672
• Collaborator: The Physicians' Services Incorporated Foundation (Other), California Pacific Medical Center (Other), Sunnybrook Health Sciences Centre (Other), Canadian Institutes of Health Research (CIHR) (Other)
• Enrollment: 265
• Location: 1
• Arms: 6
• Duration (Months): 39
• Patients Per Site Per Month: 6.8

Study Details

Study Description

Brief Summary

Purpose: NABT: To compare five widely available nitrate formulations: (1) 15 of nitroglycerin (NTG) ointment, (2) 0.3 mg and (3) 0.6 mg of sublingual NTG, (4) 20 mg of isosorbide mononitrate (an oral tablet), and (5) 160 mg of glycerol trinitrate (a patch), for their efficacy on markers of bone formation and resorption and for the incidence and severity of headache they cause.

Hypothesis: There is one ideal nitrate preparation which balances the clinical efficacy in bone remodeling against the common side effect of headache.

NABT-B: To determine if nitrates affect markers of bone formation (serum BALP and P1NP) and resorption (serum CTX and urine NTX) in women who have recently discontinued treatment with alendronate, risedronate or zoledronate.

Condition or Disease	Intervention/Treatment	Phase
Osteoporosis	Drug: Nitrates (NABT Main trial); Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 265 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Nitrates and Bone Turnover (NABT): Trial to Select the Best Nitrate Preparation
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nitrol Nitroglycerin Ointment 2% USP	Drug: Nitrates (NABT Main trial); nitroglycerin; isosorbide mononitrate; Other Names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period
Active Comparator: Nitro-Dur Nitroglycerin Extended Release Patch 160mg	Drug: Nitrates (NABT Main trial); nitroglycerin; isosorbide mononitrate; Other Names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period
Active Comparator: Nitrostat 1 Nitroglycerin 0.3mg Sublingual Tablet	Drug: Nitrates (NABT Main trial); nitroglycerin; isosorbide mononitrate; Other Names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period
Active Comparator: Nitrostat 2 Nitroglycerin 0.6mg Sublingual Tablet	Drug: Nitrates (NABT Main trial); nitroglycerin; isosorbide mononitrate; Other Names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period
Active Comparator: ISMO Isosorbide Mononitrate 20mg Oral Tablet	Drug: Nitrates (NABT Main trial); nitroglycerin; isosorbide mononitrate; Other Names: NABT-B Sub-Study: Nitroglycerin Ointment 2%: 15mg of NTG ointment for a 3 month period
Placebo Comparator: Placebo Placebo Ointment	Other: Placebo; Placebo ointment

Outcome Measures

Primary Outcome Measures

1. Bone Turnover Markers [3 months]

   Markers of Bone Formation: Serum Procollagen type 1 amino- terminal propeptide (P1NP) Serum Osteocalcin (OC) Serum Bone-specific alkaline phosphatase (BALP) Markers of Bone Resorption: - Serum C-telopeptides of collagen cross-links (CTX)

Secondary Outcome Measures

1. Headache [Run-in phase - 2 days]

   Severity of headaches. Subjects recorded the severity of headaches upon awakening every day during the run-in phase using a visual analogue scale (VAS). The scale is represented by a line (continuum) 10 cm long. Subjects were asked to make a vertical line along the continuum to indicate the severity of their headache each morning upon awakening. The score is recorded in cm from "0" to "10". A vertical line marked at "0" means no headache (score recorded = "0"), a vertical line marked at "10" means a terrible headache (score recorded = "10").

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

NABT:

• Women aged 50 years and older whose last menstrual period occurred at least 3 years ago

• Women without a uterus will be eligible after age 55

NABT-B:

• Women aged 50 years and older whose last menstrual period occurred at least 3 years ago

• Women without a uterus will be eligible after age 55

• Previously treated with alendronate but stopped within 2 years of study commencement; or previously treated with risedronate but stopped within 1 year of study commencement; or previously treated with zoledronate.

Exclusion Criteria:

NABT:

• A previous fracture of the hip, wrist, spine or ankle within the last 3 months; or a diagnosis of osteoporosis;

• A history of bone disorders such as hyperparathyroidism or Paget's disease;

• Treatment within 12 months of study entry with any agent that may influence bone metabolism including any hormone, anti-estrogen or raloxifene and prednisone (equivalent to 5 mg/d for 12 months or greater);

• Treatment with any antiresorptive agent, including alendronate, risedronate, etidronate or denosumab use for at least four weeks within the last three years;

• Previous treatment with intravenous zoledronate or parathyroid hormone;

• Current treatment with nitrates;

• A history of migraine headaches;

• A history of angina or cardiovascular disease;

• Inability to give informed consent;

• Hypersensitivity to nitroglycerin.

NABT-B:

• A previous fracture of the hip, wrist, spine or ankle; or a self-reported diagnosis of osteoporosis;

• A history of bone disorders such as hyperparathyroidism or Paget's disease;

• Treatment within 12 months of study entry with any agent that may influence bone metabolism including any hormone, anti-estrogen or raloxifene and prednisone (equivalent to 5 mg/d for 12 months or greater);

• Treatment with etidronate or denosumab use for at least four weeks within the last three years and any previous treatment with parathyroid hormone;

• Current treatment with nitrates;

• A history of migraine headaches;

• A history of angina or cardiovascular disease;

• Inability to give informed consent;

• Hypersensitivity to nitroglycerin.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Women's College Research Institute/Women's College Hospital	Toronto	Ontario	Canada	M5G 1N8

Sponsors and Collaborators

• University of Toronto
• The Physicians' Services Incorporated Foundation
• California Pacific Medical Center
• Sunnybrook Health Sciences Centre
• Canadian Institutes of Health Research (CIHR)

Investigators

• Principal Investigator: Sophie A Jamal, MD,PhD,FRCPC, Women's College Research Institute/Women's College Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Jamal SA, Browner WS, Bauer DC, Cummings SR. Intermittent use of nitrates increases bone mineral density: the study of osteoporotic fractures. J Bone Miner Res. 1998 Nov;13(11):1755-9.
• Jamal SA, Cummings SR, Hawker GA. Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial. J Bone Miner Res. 2004 Sep;19(9):1512-7. Epub 2004 Jul 26.
• Jamal SA, Goltzman D, Hanley DA, Papaioannou A, Prior JC, Josse RG. Nitrate use and changes in bone mineral density: the Canadian Multicentre Osteoporosis Study. Osteoporos Int. 2009 May;20(5):737-44. doi: 10.1007/s00198-008-0727-7. Epub 2008 Sep 18. Retraction in: Osteoporos Int. 2016 Dec 1;:.
• Jamal SA, Hamilton CJ, Eastell R, Cummings SR. Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial. JAMA. 2011 Feb 23;305(8):800-7. doi: 10.1001/jama.2011.176. Retraction in: Eastell R, Hamilton CJ, Cummings SR. JAMA. 2016 Jan 26;315(4):418-9.
• Wimalawansa SJ, Grimes JP, Wilson AC, Hoover DR. Transdermal nitroglycerin therapy may not prevent early postmenopausal bone loss. J Clin Endocrinol Metab. 2009 Sep;94(9):3356-64. doi: 10.1210/jc.2008-2225. Epub 2009 Jun 23.

• Responsible Party: Sophie Jamal, Associate Professor/Endocrinologist, University of Toronto
• ClinicalTrials.gov Identifier: NCT01387672
• Other Study ID Numbers: 062011
• First Posted: Jul 4, 2011
• Last Update Posted: May 8, 2015
• Last Verified: May 1, 2015

• Keywords provided by Sophie Jamal, Associate Professor/Endocrinologist, University of Toronto: postmenopausal; osteoporosis; bone turnover; nitrate; headache
• Additional relevant MeSH terms: Osteoporosis; Nitroglycerin

Study Results

Participant Flow

Pre-assignment Detail	Initial run-in period-subjects received, in random order, each of the 5 nitrate formulations for 2 days with a 2 day wash out period between formulations. There were 265 subjects enrolled in the run-in phase of the study. Out of those, 229 subjects entered the treatment phase of the study, where they were randomized to one of the 6 treatment arms.

Arm/Group Title	ISMO - Treatment Arm 1	Patch (Nitro-Dur) - Treatment Arm 2	Ointment (Nitrol) - Treatment Arm 3	0.3 Sublingual (Nitrostat 1) - Treatment Arm 4	0.6 Sublingual (Nitrostat 2) - Treatment Arm 5	Placebo Ointment - Treatment Arm 6
Arm/Group Description	Isosorbide Mononitrate 20mg Oral Tablet Nitrates (NABT Main trial)	Nitroglycerin Extended Release Patch 160mg Nitrates (NABT Main trial)	Nitroglycerin Ointment 2% USP Nitrates (NABT Main trial)	Nitroglycerin 0.3mg Sublingual Tablet Nitrates (NABT Main trial)	Nitroglycerin 0.6mg Sublingual Tablet Nitrates (NABT Main trial)	Placebo Ointment Nitrates (NABT Main trial)
Period Title: Overall Study
STARTED	39	38	38	39	38	37
COMPLETED	32	31	33	35	34	37
NOT COMPLETED	7	7	5	4	4	0

Baseline Characteristics

Arm/Group Title	ISMO - Treatment Arm 1	Patch (Nitro-Dur) - Treatment Arm 2	Ointment (Nitrol) - Treatment Arm 3	0.3 Sublingual (Nitrostat 1) - Treatment Arm 4	0.6 Sublingual (Nitrostat 2) - Treatment Arm 5	Placebo Ointment - Treatment Arm 6	Total
Arm/Group Description	Isosorbide Mononitrate 20mg Oral Tablet Nitrates (NABT Main trial)	Nitroglycerin Extended Release Patch 160mg Nitrates (NABT Main trial)	Nitroglycerin Ointment 2% USP Nitrates (NABT Main trial)	Nitroglycerin 0.3mg Sublingual Tablet Nitrates (NABT Main trial)	Nitroglycerin 0.6mg Sublingual Tablet Nitrates (NABT Main trial)	Placebo Ointment Placebo: Placebo ointment Nitrates (NABT Main trial)	Total of all reporting groups
Overall Participants	39	38	38	39	38	37	229
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	19 48.7%	21 55.3%	20 52.6%	23 59%	23 60.5%	20 54.1%	126 55%
>=65 years	20 51.3%	17 44.7%	18 47.4%	16 41%	15 39.5%	17 45.9%	103 45%
Sex: Female, Male (Count of Participants)
Female	39 100%	38 100%	38 100%	39 100%	38 100%	37 100%	229 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Canada	39 100%	38 100%	38 100%	39 100%	38 100%	37 100%	229 100%

Outcome Measures

1. Primary Outcome

Title	Bone Turnover Markers
Description	Markers of Bone Formation: Serum Procollagen type 1 amino- terminal propeptide (P1NP) Serum Osteocalcin (OC) Serum Bone-specific alkaline phosphatase (BALP) Markers of Bone Resorption: - Serum C-telopeptides of collagen cross-links (CTX)
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

One subject from the Treatment Arm 3 had outlier bone turnover markers values and was excluded from the analysis. Total number of subjects analyzed in Treatment Arm 3 was therefore 32.

Arm/Group Title	ISMO - Treatment Arm 1	Patch (Nitro-Dur) - Treatment Arm 2	Ointment (Nitrol) - Treatment Arm 3	0.3 Sublingual (Nitrostat 1) - Treatment Arm 4	0.6 Sublingual (Nitrostat 2) - Treatment Arm 5	Placebo Ointment - Treatment Arm 6
Arm/Group Description	Isosorbide Mononitrate 20mg Oral Tablet Nitrates (NABT Main trial)	Nitroglycerin Extended Release Patch 160mg Nitrates (NABT Main trial)	Nitroglycerin Ointment 2% USP Nitrates (NABT Main trial)	Nitroglycerin 0.3mg Sublingual Tablet Nitrates (NABT Main trial)	Nitroglycerin 0.6mg Sublingual Tablet Nitrates (NABT Main trial)	Placebo Ointment Placebo: Placebo ointment Nitrates (NABT Main trial)
Measure Participants	32	31	32	35	34	37
P1NP	-4.627 (16.191)	-0.405 (20.289)	-4.297 (16.236)	-6.126 (16.093)	2.941 (36.843)	-1.635 (16.749)
OC	-3.244 (12.049)	3.796 (33.601)	-4.481 (14.823)	1.046 (21.818)	1.033 (17.931)	4.247 (22.088)
BALP	-5.023 (11.824)	-0.541 (20.738)	-7.426 (11.056)	-7.000 (19.011)	-3.686 (17.435)	-1.648 (21.523)
CTX	-5.844 (26.084)	-1.025 (32.163)	-9.699 (27.299)	-0.666 (37.945)	-1.380 (52.248)	-1.783 (28.063)

2. Secondary Outcome

Title	Headache
Description	Severity of headaches. Subjects recorded the severity of headaches upon awakening every day during the run-in phase using a visual analogue scale (VAS). The scale is represented by a line (continuum) 10 cm long. Subjects were asked to make a vertical line along the continuum to indicate the severity of their headache each morning upon awakening. The score is recorded in cm from "0" to "10". A vertical line marked at "0" means no headache (score recorded = "0"), a vertical line marked at "10" means a terrible headache (score recorded = "10").
Time Frame	Run-in phase - 2 days

Outcome Measure Data

Analysis Population Description

The mean headache score considering all subjects in each of the treatment/formulation group was calculated.

Arm/Group Title	Run-in Phase
Arm/Group Description	During the run-in phase subjects received, in random order, each of the 5 nitrate formulations for 2 days with a 2 day wash out period between formulations. The severity of headaches was recorded, by subjects, upon awakening, every day during the run in phase using a visual analog scale (VAS).
Measure Participants	238
ISMO	2.1 (2.64)
Patch	3.1 (2.98)
Ointment	1.5 (2.12)
0.3 Sublingual	0.36 (1.18)
0.6 Sublingual	0.6 (1.62)

Adverse Events

Time Frame	The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
Arm/Group Title	ISMO - Treatment Arm 1		Patch (Nitro-Dur) - Treatment Arm 2		Ointment (Nitrol) - Treatment Arm 3		0.3 Sublingual (Nitrostat 1) - Treatment Arm 4		0.6 Sublingual (Nitrostat 2) - Treatment Arm 5		Placebo Ointment- Treatment Arm 6
Arm/Group Description	Isosorbide Mononitrate 20mg Oral Tablet Nitrates (NABT Main trial)		Nitroglycerin Extended Release Patch 160mg Nitrates (NABT Main trial)		Nitroglycerin Ointment 2% USP Nitrates (NABT Main trial)		Nitroglycerin 0.3mg Sublingual Tablet Nitrates (NABT Main trial)		Nitroglycerin 0.6mg Sublingual Tablet Nitrates (NABT Main trial)		Placebo Ointment Placebo: Placebo ointment Nitrates (NABT Main trial)
All Cause Mortality
	ISMO - Treatment Arm 1		Patch (Nitro-Dur) - Treatment Arm 2		Ointment (Nitrol) - Treatment Arm 3		0.3 Sublingual (Nitrostat 1) - Treatment Arm 4		0.6 Sublingual (Nitrostat 2) - Treatment Arm 5		Placebo Ointment- Treatment Arm 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	ISMO - Treatment Arm 1		Patch (Nitro-Dur) - Treatment Arm 2		Ointment (Nitrol) - Treatment Arm 3		0.3 Sublingual (Nitrostat 1) - Treatment Arm 4		0.6 Sublingual (Nitrostat 2) - Treatment Arm 5		Placebo Ointment- Treatment Arm 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		0/38 (0%)		0/38 (0%)		1/39 (2.6%)		1/38 (2.6%)		0/37 (0%)
Nervous system disorders
Transient Global Amnesia	0/39 (0%)	0	0/38 (0%)	0	0/38 (0%)	0	0/39 (0%)	0	1/38 (2.6%)	1	0/37 (0%)	0
Vascular disorders
Stroke	0/39 (0%)	0	0/38 (0%)	0	0/38 (0%)	0	1/39 (2.6%)	1	0/38 (0%)	0	0/37 (0%)	0
Other (Not Including Serious) Adverse Events
	ISMO - Treatment Arm 1		Patch (Nitro-Dur) - Treatment Arm 2		Ointment (Nitrol) - Treatment Arm 3		0.3 Sublingual (Nitrostat 1) - Treatment Arm 4		0.6 Sublingual (Nitrostat 2) - Treatment Arm 5		Placebo Ointment- Treatment Arm 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/39 (43.6%)		21/38 (55.3%)		17/38 (44.7%)		10/39 (25.6%)		12/38 (31.6%)		6/37 (16.2%)
Gastrointestinal disorders
Nausea	1/39 (2.6%)	1	2/38 (5.3%)	2	0/38 (0%)	0	2/39 (5.1%)	2	1/38 (2.6%)	1	0/37 (0%)	0
Nervous system disorders
Headache	17/39 (43.6%)	17	21/38 (55.3%)	21	17/38 (44.7%)	17	10/39 (25.6%)	10	12/38 (31.6%)	112	6/37 (16.2%)	6
Dizziness	1/39 (2.6%)	1	2/38 (5.3%)	2	1/38 (2.6%)	1	0/39 (0%)	0	2/38 (5.3%)	2	0/37 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.