Welchol (Colesevelam Hcl) Drug Information: Clinical Pharmacology

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May 27, 2012

Welchol

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CLINICAL PHARMACOLOGY

Mechanism of Action

Primary Hyperlipidemia

Colesevelam hydrochloride, the active pharmaceutical ingredient in WELCHOL, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged.

Type 2 Diabetes Mellitus

The mechanism by which WELCHOL improves glycemic control is unknown.

Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of WELCHOL was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to WELCHOL, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment.

Pharmacokinetics

Absorption

Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.

Distribution

Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.

Metabolism

Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.

Excretion

In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14C-labeled colesevelam hydrochloride dose was excreted in the urine.

Drug Interactions

Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies. In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride. Therefore, an in vivo pharmacokinetic interaction of WELCHOL with these drugs is unlikely. WELCHOL was found to have no significant effect on the bioavailability of digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, pioglitazone, and warfarin. The results of additional in vivo drug interactions of WELCHOL are presented in Table 5.

Drug interactions between WELCHOL and other commonly co-administered drugs in patients with type 2 diabetes (including rosiglitazone maleate, glimepiride, glipizide, sitagliptin phosphate, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, sustained-release formulations of anti-diabetic and anti-hypertensive drugs, and aspirin) have not been evaluated.

Table 5 : Mean Change in Drug Exposure (AUC0-∞ and Cmax) when Administered with WELCHOL (3.75 g)a

Drug	Dose	Co-administered		1 hr prior to WELCHOL		4 hr prior to WELCHOL
Drug	Dose	AUC0-∞	Cmax	AUC0-∞	Cmax	AUC0-∞	Cmax
Verapamil sustainedrelease	240 mg	-31%	-11%	N/A	N/A	N/A	N/A
Glyburide^b	3 mg	-32%	-47%	-20%	-15%	-7%	4%
Levothyroxine^b	600 μg	-22%	-33%	6%	-2%	1%	8%
Norethindrone*^b	1 mg	-1%	-20%	5%	-3%	6%	7%
Ethinyl Estradiol* ^b	0.035 mg	-24%	-24%	-18%	-1%	-12%	0%
Repaglinide	2 mg	-7%	-19%	-6%	-1%	N/A	N/A
Cyclosporine	200 mg	-34%	-44%	N/A	N/A	N/A	N/A
^a With verapamil, the dose of WELCHOL was 4.5 g ^b Should be administered at least 4 hours prior to WELCHOL. [See DRUG INTERACTIONS] * Oral contraceptive containing norethindrone and ethinyl estradiol. N/A – Not Available

Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.

Clinical Studies

Primary Hyperlipidemia

WELCHOL reduces TC, LDL-C, apolipoprotein B (Apo B), and non-HDL-C when administered alone or in combination with a statin in patients with primary hyperlipidemia.

Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to WELCHOL was achieved within 2 weeks and was maintained during long-term therapy.

Monotherapy

In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), WELCHOL was given for 24 weeks in divided doses with the morning and evening meals.

As shown in Table 6, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. WELCHOL at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both WELCHOL doses but the changes were not statistically different from placebo.

Table 6 : Response to WELCHOL Monotherapy in a 24-Week Trial - Percent Change in Lipid Parameters from Baseline

Grams/Day	N	TC	LDL-C	Apo B	HDL-Ca	Non-HDL-C	TG^a
Placebo	88	+1	0	0	–1	+1	+5
3.8 g (6 tablets)	95	–7*	–15*	–12*	+3*	–10*	+10
4.5 g (7 tablets)	94	–10*	–18*	–12*	+3	–13*	+9
*p < 0.05 for lipid parameters compared to placebo, for Apo B compared to baseline. ^a Median % change from baseline.

In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), WELCHOL 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another.

Combination Therapy

Co-administration of WELCHOL and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 7, WELCHOL doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.

Table 7 : Response to WELCHOL in Combination with Atorvastatin, Simvastatin, or Lovastatin - Percent Change in Lipid Parameters

Dose/Day	N	TC	LDL-C	Apo B	HDL-C^a	Non-HDL-C	TG^a
Atorvastatin Trial (4-week)
Placebo	19	+4	+3	–3	+4	+4	+10
Atorvastatin 10 mg	18	–27*	–38*	–32*	+8	–35*	–24*
WELCHOL 3.8 g/ Atorvastatin 10 mg	18	–31*	–48*	–38*	+11	–40*	–1
Atorvastatin 80 mg	20	–39*	–53*	–46*	+6	–50*	–33*
Simvastatin Trial (6-week)
Placebo	33	–2	–4	–4*	–3	–2	+6*
Simvastatin 10 mg	35	–19*	–26*	–20*	+3*	–24*	–17*
WELCHOL 3.8 g/	34	–28*	–42*	–33*	+10*	–37*	–12*
Simvastatin 10 mg
Simvastatin 20 mg	39	–23*	–34*	–26*	+7*	–30*	–12*
WELCHOL 2.3 g/ Simvastatin 20 mg	37	–29*	–42*	–32*	+4*	–37*	–12*
Lovastatin Trial (4-week)
Placebo	26	+1	0	0	+1	+1	+1
Lovastatin 10 mg	26	–14*	–22*	–16*	+5	–19*	0
WELCHOL 2.3 g/Lovastatin 10 mg	27	–21*	–34*	–24*	+4	–27*	–1
Together
WELCHOL 2.3 g/Lovastatin 10 mg Apart	23	–21*	–32*	–24*	+2	–28*	–2
*p < 0.05 for lipid parameters compared to placebo, for Apo B compared to baseline. ^a Median % change from baseline.

In all 3 studies, the LDL-C reduction achieved with the combination of WELCHOL and any given dose of statin therapy was statistically superior to that achieved with WELCHOL or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of WELCHOL 3.8 g and atorvastatin 10 mg.

The effect of WELCHOL when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C ≥ 115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label run-in period and then randomly assigned to receive fenofibrate 160 mg plus either WELCHOL 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 8.

Table 8 : Response to WELCHOL Added to Fenofibrate in Patients with Mixed Hyperlipidemia (Mean % Change from Treated Baselineb at 6 Weeks)

Treatment	N	TC	LDL-C	Apo	HDL-C	Non-HDL-	TGa
Placebo + Fenofibrate 160 mg	61	2	2	1	-1	2	-3
WELCHOL + Fenofibrate 160 mg	61	-6*	-10*	-7*	0	-8*	6
* p ≤ 0.0002 compared to placebo. ^a For triglycerides, median % change from baseline. ^b Treated Baseline: following 8-week treatment with open-label fenofibrate 160 mg.

Pediatric Therapy

The safety and efficacy of WELCHOL in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (heFH), taking a stable dose of an FDA-approved statin (with LDL-C > 130 mg/dL) or naïve to lipid-lowering therapy (with LDL-C > 160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL.

During the double-blind treatment period, patients were assigned randomly to treatment: WELCHOL 3.8 g/day (n=64), WELCHOL 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, WELCHOL 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).

Table 9 : Response to WELCHOL 3.8 g Compared to Placebo in Pediatric Patients 10-17 Years of Age – Mean Percent Change in Lipid Parameters from Baseline to Week 8

Treatment Difference	TC (N=128)	LDL-C (N=128)	Apo B (N=124)	HDL-C (N=128)	Non-HDL-C (N=128)	TG^a (N=128)
WELCHOL 3.8 g vs Placebo	-7*	-13*	-8*	+6*	–11 *	+5
*p ≤ 0.05 for lipid parameters compared to placebo Values represent LS mean. Only patients with values at both study baseline and endpoint are included in this table. Study baseline was defined as the last value measured before or on Day 1 prior to the first dose of randomized study medication. ^a For triglycerides, median % change from baseline. Results were based on the ITT population with LOCF

During the open-label treatment period patients were treated with WELCHOL 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8.

Type 2 Diabetes Mellitus

WELCHOL has been studied in combination with metformin, sulfonylureas, and insulin. WELCHOL has not been studied as monotherapy.

The efficacy of WELCHOL 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 3 double-blind, placebo-controlled add-on therapy trials involving a total of 1018 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. WELCHOL and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone.

In these studies, the overall mean age was 57 years (range 24-81 years), 47% were women, and 59% of the patients were Caucasian, 23% were Hispanic, 14% were Black, 3% were Asian, and 1% were of other racial groups. Statin use at baseline was reported in 42% of the WELCHOL-treated patients and 50% of the placebo-treated patients. In all 3 pivotal add-on therapy trials, treatment with WELCHOL resulted in a statistically significant reduction in A1C of 0.5% compared to placebo. Similar placebo-corrected reductions in A1C occurred in patients who received WELCHOL in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other anti-diabetic agents. In the metformin and sulfonylurea trials, treatment with WELCHOL also resulted in statistically significant reductions in fasting plasma glucose (FPG) of 14 mg/dL compared to placebo.

WELCHOL had consistent effects on A1C across subgroups of age, gender, race, body mass index, and baseline A1C. WELCHOL's effects on A1C were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone).

The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), and 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, WELCHOL treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. WELCHOL treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin and patients on a sulfonylurea, but not in the study of patients on metformin. The clinical significance of these increases is unknown. WELCHOL is contraindicated in patients with TG levels > 500 mg/dL [See CONTRAINDICATIONS] and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended [See WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Body weight did not significantly increase from baseline with WELCHOL therapy, compared with placebo, in any of the 3 pivotal clinical studies.

Add-on Combination Therapy with Metformin

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). A total of 60% of these patients were receiving ≥ 1,500 mg/day of metformin. In combination with metformin, WELCHOL resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 10). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 11). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with WELCHOL compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for WELCHOL and -0.3 kg for placebo.

Table 10 : Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes

	Total Patient Population		Metformin Alone		Metformin in Combination with Other Oral Anti-Diabetic Agents
	WELCHOL 3.8 g/day	Placebo	WELCHOL 3.8 g/day	Placebo	WELCHOL 3.8 g/day	Placebo
A1C (%), Mean
N	148	152	79	76	69	76
Baseline	8.1	8.1	8.2	8.2	8.1	8.0
Change from baseline^a	-0.4	0.2	-0.4	0.0	-0.4	0.3
Treatment difference (p-value)	-0.5 (p<	0.001)	-0.5	(p=0.002)	-0.6 (p<	0.001)
FPG (mg/dL), Mean
N	149	152	79	76	70	76
Baseline	178	174	184	180	171	168
Change from baseline^a	-3	11	-7	8	0	13
Treatment difference (p-value)	-14	(p=0.01)	-14	(p=0.07)	-14	(p=0.10)
^a Least-squares mean change calculated from an Analysis of Covariance model. A1C = hemoglobin A1C, FPG = fasting plasma glucose

Table 11 : Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes

Dose/Day	N†	TC	LDL-C	Apo B	HDL-C	Non-HDL-C	TG^a
Total Patient Population
WELCHOL 3.8 g	125	-4*	-12*	-4*	1	-6*	12
Placebo	126	3	4	4	0	5	7
Metformin Alone
WELCHOL 3.8 g	66	-3	-9	-2	1	-4	15
Placebo	61	2	0	1	-2	4	8
Metformin in Combination with Other Oral Anti-diabetic Agents
WELCHOL 3.8 g	59	-6*	-15*	-6*	1	-7*	8
Placebo	65	4	7	7	2	6	5
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials) ^a Median % change from baseline. †The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on Combination Therapy with Sulfonylurea

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). A total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with a sulfonylurea, WELCHOL resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 12). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 13). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with WELCHOL compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for WELCHOL and -0.4 kg for placebo.

Table 12 : Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Sulfonylurea in Patients with Type 2 Diabetes

	Total Patient Population		Sulfonylurea Alone		Sulfonylurea in Combination with Other Oral Anti-diabetic Agents
	WELCHOL 3.8 g/day	Placebo	WELCHOL 3.8 g/day	Placebo	WELCHOL 3.8 g/day	Placebo
A1C (%), Mean
n	218	218	69	80	149	138
Baseline	8.2	8.3	8.2	8.4	8.2	8.3
Change from baseline^a	-0.3	0.2	-0.3	0.5	-0.4	0.0
Treatment difference (p-value)	-0.5 (p < 0.001)		-0.8 (p < 0.001)		-0.4 (p < 0.001)
FPG (mg/dL), Mean
n	218	217	70	80	148	137
Baseline	177	181	181	186	175	178
Change from baseline^a	-4	10	3	15	-11	4
Treatment difference (p-value)	-14 (p=0.009)		-12 (p=0.18)		-14 (p=0.03)
^a Least-squares mean change calculated from an Analysis of Covariance model. A1C = hemoglobin A1C, FPG = fasting plasma glucose

Table 13 : Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination With Sulfonylurea in Patients with Type 2 Diabetes

Dose/Day	N†	TC	LDL-C	Apo B	HDL-C	Non-HDL-C	TG^a
Total Patient Population
WELCHOL 3.8 g	186	-5*	-16*	-6*	1	-6*	20*
Placebo	193	0	1	1	0	1	1
Sulfonylurea Alone
WELCHOL 3.8 g	57	-5	-14*	-5	-1	-6	17
Placebo	68	0	1	1	1	0	-1
Sulfonylurea in Combination with Other Oral Anti-diabetic Agents
WELCHOL 3.8 g	129	-5	-18*	-7*	1	-6	21*
Placebo	125	0	0	1	0	1	2
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials) ^a Median % change from baseline. † The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on Combination Therapy with Insulin

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the WELCHOL group and 65 units in the placebo group. In combination with insulin, WELCHOL resulted in a statistically significant placebo-corrected reduction in A1C (Table 14). WELCHOL also reduced LDL-C and Apo B, but increased serum TG (Table 15). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with WELCHOL compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for WELCHOL and 0.2 kg for placebo.

Table 14 : Glycemic Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes

	Total Patient Population		Insulin Alone		Insulin in Combination with Oral Anti-diabetic Agents
	WELCHOL 3.8 g/day	Placebo	WELCHOL 3.8 g/day	Placebo	WELCHOL 3.8 g/day	Placebo
A1C (%), Mean
n	144	136	54	55	90	81
Baseline	8.3	8.2	8.2	8.3	8.3	8.2
Change from baselinea	-0.4	0.1	-0.4	0.2	-0.4	0.0
Treatment difference (p-value)	-0.5 (p < 0.001)		-0.6 (p < 0.001)		-0.4 (p < 0.001)
FPG (mg/dL), Mean
n	144	136	54	55	90	81
Baseline	165	151	165	163	165	143
Change from baselinea	2	16	8	17	-4	14
^a Least-squares mean change calculated from an Analysis of Covariance model. A1C = hemoglobin A1C, FPG = fasting plasma glucose

Table 15 : Percent Change in Lipid Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes

Dose/Day	N†	TC	LDL-C	Apo B	HDL-C	Non-HDL-C	TG^a
Total Patient Cohort
WELCHOL 3.8 g	129	-3	-12*	-4	-1	-3	23*
Placebo	121	1	1	1	0	1	0
Insulin Alone
WELCHOL 3.8 g	46	-3	-12	-5	0	-3	19
Placebo	48	2	4	2	3	2	-2
Insulin in Combination with Oral Anti-diabetic Agents
WELCHOL 3.8 g	83	-4	-13	-4	-1	-3	25*
Placebo	73	-1	-3	0	-1	-1	2
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials) ^a Median % change from baseline. † The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.