Drug Trials Snapshot: NATPARA (parathyroid hormone)

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the NATPARA Package Insert for complete information.

NATPARA (parathyroid hormone)
Nat-pah-ruh
NPS Pharmaceuticals
Approval date: January 23, 2015

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DRUG TRIALS SUMMARY: 

What is the drug for?

NATPARA is a prescription parathyroid hormone used with calcium and vitamin D to control low blood calcium (hypocalcemia) in adults with low parathyroid hormone (PTH) blood levels (hypoparathyroidism). NATPARA is only for people who do not respond well to treatment with calcium and active forms of vitamin D alone, because it may increase the possible risk of bone cancer, known as osteosarcoma.

How do I use this drug?

Natpara is administered by injection one time each day in your thigh just under your skin. You should use NATPARA according to the instructions provided in the Instructions for Use document and follow the advice received from your doctor. 

What are the benefits of this drug?

NATPARA was more effective than a placebo in achieving a combined goal: reducing the amount required of oral calcium and vitamin D, while maintaining serum calcium levels.

What are the benefits of this drug (results of trials used to assess efficacy)?

Efficacy was defined as the percentage of subjects who at Week 24 achieved all 3 components of the composite endpoint: at least a 50% reduction from baseline of active forms of vitamin D, at least a 50% reduction from baseline of oral calcium, and an albumin-corrected total serum calcium concentration between 7.5 mg/dL and 10.6 mg/dL.

Table 3 shows the proportion of subjects meeting all 3 components of the composite endpoint at end of treatment. NATPARA showed a clinically and statistically significant difference in the efficacy endpoint compared to placebo. At the end of treatment, 46/84 (54.8%) subjects treated with NATPARA achieved the efficacy endpoint versus 1/40 (2.5%) with placebo (p<0.001). At the end of treatment, 35/84 (41.7%) NATPARA subjects were independent of active vitamin D treatment and were receiving no more than 500 mg of calcium citrate, compared with 1/40 (2.5%) placebo subjects (p<0.001). There was no difference in the proportion of patients with a calcium level between 7.5 mg and 10.6 mg at end of treatment between subjects randomized to NATPARA and placebo.

Table 3. Efficacy Endpoint Based on Investigator-prescribed Data – ITT Population

Efficacy Endpoint	Placebo (N=40)	NATPARA (N=84)
Responder at End of Treatment, based on investigator-prescribed data - n (%)	1 (2.5)	46 (54.8) (p <>a

^aBased on Fisher’s exact test
*Response = at least a 50% reduction from baseline in the dose of active vitamin D + at least a 50% reduction from baseline in the dose of oral calcium supplementation + an albumin-corrected total serum calcium concentration between 7.5 mg/dL and 10.6 mg/dL
Source: Package Insert, Section 14, Table 6

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

•  
• Sex:  The number of patients in the main trial was small and the majority were female. NATPARA appeared to work similarly in men and women.
• Race:  The number of non-white patients was limited; therefore, differences in response to NATPARA between white and non-white patients could not be determined.

• Age:  The number of patients above 65 years of age was limited; therefore, differences in response to NATPARA between patients above and below 65 years of could not be determined.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age?

Table 4. Efficacy Analysis by Demographic Subgroup

				Placebo	NATPARA	p value
				(N=40)	(N=84)
				n (%)	n (%)
Age	<65>		Non-Responder	35 (97.2%)	38 (47.5%)
			Responder	1 (2.8%)	42 (52.5%)	<>
	≥65 Years		Non-Responder	4 (100%)	0 (0%)
			Responder	0 (0%)	4 (100%)	0.029
Sex	Male		Non-Responder	7 (100%)	9 (47.4%)
			Responder	0 (0%)	10 (52.6%)	0.023
	Female		Non-Responder	32 (97%)	29 (44.6%)
			Responder	1 (3%)	36 (55.38%)	<>
Race	White	Non-Responder		38 (97.4%)	35 (43.8%)
		Responder		1 (2.6%)	45 (56.3%)	<>
	Other	Non-Responder		1 (100%)	3 (75%)
		Responder		0 (0%)	1 (25%)	1

Source: Adapted from Medical Review, Table 23

What are the possible side effects?

NATPARA may cause serious side effects, including:

• Possible bone cancer (osteosarcoma). During animal drug testing, NATPARA caused some rats to develop a bone cancer called osteosarcoma. It is not known if people who take NATPARA will have a higher chance of getting osteosarcoma. NATPARA is only available through the NATPARA Risk Evaluation and Mitigation Strategy (REMS) Program. The purpose of the program is to inform patients about the potential risk of osteosarcoma associated with the use of NATPARA.
• High blood calcium (hypercalcemia)
• Low blood calcium (hypocalcemia)

The most common side effects associated with NATPARA that occurred more commonly on NATPARA than on placebo were a sensation of tingling or burning (paresthesia), low blood calcium (hypocalcemia), headache, hypercalcemia (high blood calcium), and nausea. 

NAPTARA and other medicines may affect each other causing side effects. These include digoxin, alendronate, calcium supplements or food products that contain calcium, or active vitamin D.

What are the possible side effects (results of trials used to assess safety)?
The adverse reactions associated with NATPARA occurring in greater than 15% of individuals were: paresthesia, hypocalcemia, headache, hypercalcemia, and nausea. Table 5 lists common adverse reactions associated with NATPARA use. 

Table 5. Common Adverse Reactions associated with NATPARA use in Subjects with Hypoparathyroidism

Adverse Reaction	Placebo (N=40) %	NATPARA (N=84) %
Paraesthesia	25	31
Hypocalcemia*	23	27
Headache	23	25
Hypercalcemia*	3	19
Nausea	18	18
Hypoaesthesia	10	14
Diarrhea	3	12
Vomiting	0	12
Arthralgia	10	11
Hypercalciuria*	8	11
Pain in extremity	8	10
Upper respiratory tract infection	5	8
Abdominal pain upper	3	7
Sinusitis	5	7
Blood 25-hydroxycholecalciferol decreased	3	6
Hypertension	5	6
Hypoaesthesia facial	3	6
Neck pain	3	6

* Hypocalcemia combines reported events of hypocalcemia and blood calcium decreased, hypercalciuria combines reported events of hypercalciuria and  urine calcium increased, and hypercalcemia combines reported events of hypercalcemia and blood calcium increased.

Source: NATPARA Package Insert, Table 1

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

• Sex:  The number of patients in the main trial was small and the majority were female. There did not appear to be clinically meaningful differences in the frequency of side effects between men and women.
• Race:  The number of patients in the non-white subgroup was limited. Therefore, differences among races could not be determined.
• Age:  The number of patients above 65 years of age was limited. Therefore, differences between those above and below 65 years of age could not be determined

Were there any differences in side effects among sex, race and age?

The table below summarizes serious adverse events by sex.

Table 6. Analysis of Serious Adverse Events, Safety Population

Subgroup	NATPARA (N=84) n/N (%)	Placebo N=40 n/N (%)
Any Serious Adverse Event	9/84 (10.7)	4/40 (10)
Sex
Male	1/19 (5.3)	2/7 (28.6)
Female	8/65 (12.3)	2/33 (6)

Source: Extracted from Sponsor’s Dataset

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WHO WAS IN THE STUDY?

Who participated in the clinical trials?

The FDA approved NATPARA on evidence from one main trial with a total of 124 adults who were diagnosed with established hypoparathyroidism. The study was conducted in North America, France, Italy, Belgium, Denmark, the United Kingdom, and Hungary. The study did not include patients with hypoparathyroidism caused by calcium sensing receptor mutations or patients who had hypoparathyroidism for a brief period of time immediately following surgery.

Figure 1 summarizes how many men and women were enrolled in the clinical trial.

Figure 1. Baseline Demographics by Sex

Source: Adapted from FDA Statistical Review, Table 9

Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trial. Figure 2. Baseline Demographics by Race

Figure 2. Baseline Demographics by Race  

Source: Adapted from FDA Statistical Review, Table 9

Table 1. Baseline Demographics by Race for the Intent to Treat (ITT) Population

Race	Number of Patients	Percentage
White	119	96.0%
Black	1	0.8%
Asian	2	1.6%
Native Hawaiian or Pacific Islander	1	0.8%
Other	1	0.8%

Source: Adapted from FDA Statistical Review, Table 3-3

The FDA approved NATPARA on evidence from one main trial with a total of 124 adults who were diagnosed with Hypoparathyroidism. The studies were conducted in North America, France, Italy, Belgium, Denmark, the United Kingdom, and Hungary.

Table 2: Baseline Demographics

Variable	Placebo	NATPARA	Total
	N=40	N=84	N=124
	n (%)	n (%)	n (%)
Age (years)
Mean (SD)	48.9 (13.7)	46.6 (12.2)	47.3 (12.7)
Median	52	47	48.5
Min, Max	21, 73	19, 74	19, 74
Age Category
<45>	13 (32.5)	35 (41.7)	48 (38.7)
45 to 64 years	23 (57.5)	45 (53.6)	68 (54.8)
≥65 years	4 (10)	4 (4.8)	8 (6.5)
Sex
Female	33 (82.5)	65 (77.4)	98 (79)
Male	7 (17.5)	19 (22.6)	26 (21)
Race
White	39 (97.5)	80 (95.2)	119 (96)
Black	0	1 (1.2)	1 (0.8)
Asian	1 (2.5)	1 (1.2)	2 (1.6)
Native Hawaiian/Pacific Islander	0	1 (1.2)	1 (0.8)
Other	0	1 (1.2)	1 (0.8)
Ethnicity
Hispanic or Latino	0	2 (2.4)	2 (1.6)
Not Hispanic or Latino	40 (100)	82 (97.6)	122 (98.4)

Source: Adapted from FDA Statistical Review, Table 9

How was the study designed?

NATPARA was approved by the FDA based on a main study of 124 patients. The main study was a 24-week, double blind, placebo-controlled trial. The study enrolled patients with chronic hypoparathyroidism who were taking calcium and vitamin D. Of these 124 patients, 84 patients were randomly assigned to receive NATPARA and 40 patients were randomly assigned to a placebo. Neither the patients nor the health care professionals administering the drug knew which patients were taking NATPARA and which patients were taking a placebo, until after the study was complete.

How was the study designed?

The efficacy of NATPARA was evaluated in a 24-week, randomized, double-blind, placebo-controlled, multicenter trial.  In this trial, patients with chronic hypoparathyroidism receiving calcium and active forms of vitamin D (vitamin D metabolite or analogs) were randomized (2:1) to NATPARA (n=84) or placebo (n=40).  The mean age was 47 years (range: 19 to 74 years), 79% were females, and 96% were white.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PACKAGE INSERT

MEDICAL REVIEW

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